1. Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions
Based on McMurry’s Organic Chemistry, 6th edition
©2003 Ronald Kluger
Department of Chemistry
University of Toronto
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

2. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Aldehydes and Ketones
Aldehydes and ketones are characterized by the the carbonyl functional group (C=O)
The compounds occur widely in nature as intermediates in metabolism and biosynthesis
They are also common as chemicals, as solvents, monomers, adhesives, agrichemicals and pharmaceuticals
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

3. 19.1 Naming Aldehydes and Ketones
Aldehydes are named by replacing the terminal -e of the corresponding alkane name with –al
The parent chain must contain the CHO group
The CHO carbon is numbered as C1
If the CHO group is attached to a ring, use the suffix See Table 19.1 for common names
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

4. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Naming Ketones
Replace the terminal -e of the alkane name with –one
Parent chain is the longest one that contains the ketone group
Numbering begins at the end nearer the carbonyl carbon
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

5. Ketones with Common Names
IUPAC retains well-used but unsystematic names for a few ketones
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

6. Ketones and Aldehydes as Substituents
The R–C=O as a substituent is an acyl group is used with the suffix -yl from the root of the carboxylic acid
CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl
The prefix oxo- is used if other functional groups are present and the doubly bonded oxygen is labeled as a substituent on a parent chain
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

7. 19.2 Preparation of Aldehydes and Ketones
Preparing Aldehydes
Oxidize primary alcohols using pyridinium chlorochromate
Reduce an ester with diisobutylaluminum hydride (DIBAH)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

8. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Preparing Ketones
Oxidize a 2° alcohol (see Section 17.8)
Many reagents possible: choose for the specific situation (scale, cost, and acid/base sensitivity)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

9. Ketones from Ozonolysis
Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted (see Section 7.8)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

10. Aryl Ketones by Acylation
Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst (see Section 16.4)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

11. Methyl Ketones by Hydrating Alkynes
Hydration of terminal alkynes in the presence of Hg2+ (catalyst: Section 8.5)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

12. 19.3 Oxidation of Aldehydes and Ketones
CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently
Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes (no acid)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

13. Hydration of Aldehydes
Aldehyde oxidations occur through 1,1-diols (“hydrates”)
Reversible addition of water to the carbonyl group
Aldehyde hydrate is oxidized to a carboxylic acid by usual reagents for alcohols
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

14. Ketones Oxidize with Difficulty
Undergo slow cleavage with hot, alkaline KMnO4
C–C bond next to C=O is broken to give carboxylic acids
Reaction is practical for cleaving symmetrical ketones
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

15. 19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones
Nu- approaches 45° to the plane of C=O and adds to C
A tetrahedral alkoxide ion intermediate is produced
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

16. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Nucleophiles
Nucleophiles can be negatively charged ( : Nu) or neutral ( : Nu) at the reaction site
The overall charge on the nucleophilic species is not considered
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

17. 19.5 Relative Reactivity of Aldehydes and Ketones
Aldehydes are generally more reactive than ketones in nucleophilic addition reactions
The transition state for addition is less crowded and lower in energy for an aldehyde (a) than for a ketone (b)
Aldehydes have one large substituent bonded to the C=O: ketones have two
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

18. Electrophilicity of Aldehydes and Ketones
Aldehyde C=O is more polarized than ketone C=O
As in carbocations, more alkyl groups stabilize + character
Ketone has more alkyl groups, stabilizing the C=O carbon inductively
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

19. Reactivity of Aromatic Aldehydes
Less reactive in nucleophilic addition reactions than aliphatic aldehydes
Electron-donating resonance effect of aromatic ring makes C=O less reactive electrophilic than the carbonyl group of an aliphatic aldehyde
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

20. 19.6 Nucleophilic Addition of H2O: Hydration
Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem) diols)
Hyrdation is reversible: a gem diol can eliminate water
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

21. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Relative Energies
Equilibrium generally favors the carbonyl compound over hydrate for steric reasons
Acetone in water is 99.9% ketone form
Exception: simple aldehydes
In water, formaldehyde consists is 99.9% hydrate
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

22. Base-Catalyzed Addition of Water
Addition of water is catalyzed by both acid and base
The base-catalyzed hydration nucleophile is the hydroxide ion, which is a much stronger nucleophile than water
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

23. Acid-Catalyzed Addition of Water
Protonation of C=O makes it more electrophilic
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

24. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Addition of H-Y to C=O
Reaction of C=O with H-Y, where Y is electronegative, gives an addition product (“adduct”)
Formation is readily reversible
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

25. 19.7 Nucleophilic Addition of HCN: Cyanohydrin Formation
Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)CN
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

26. Mechanism of Formation of Cyanohydrins
Addition of HCN is reversible and base-catalyzed, generating nucleophilic cyanide ion, CN
Addition of CN to C=O yields a tetrahedral intermediate, which is then protonated
Equilibrium favors adduct
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

27. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Uses of Cyanohydrins
The nitrile group (CN) can be reduced with LiAlH4 to yield a primary amine (RCH2NH2)
Can be hydrolyzed by hot acid to yield a carboxylic acid
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

28. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
19.8 Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation
Treatment of aldehydes or ketones with Grignard reagents yields an alcohol
Nucleophilic addition of the equivalent of a carbon anion, or carbanion. A carbon–magnesium bond is strongly polarized, so a Grignard reagent reacts for all practical purposes as R :  MgX +.
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

29. Mechanism of Addition of Grignard Reagents
Complexation of C=O by Mg2+, Nucleophilic addition of R : , protonation by dilute acid yields the neutral alcohol
Grignard additions are irreversible because a carbanion is not a leaving group
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

30. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Hydride Addition
Convert C=O to CH-OH
LiAlH4 and NaBH4 react as donors of hydride ion
Protonation after addition yields the alcohol
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

31. 19.9 Nucleophilic Addition of Amines: Imine and Enamine Formation
RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH)
R2NH yields enamines, R2NCR=CR2 (after loss of HOH)
(ene + amine = unsaturated amine)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

32. Mechanism of Formation of Imines
Primary amine adds to C=O
Proton is lost from N and adds to O to yield a neutral amino alcohol (carbinolamine)
Protonation of OH converts into water as the leaving group
Result is iminium ion, which loses proton
Acid is required for loss of OH – too much acid blocks RNH2
Note that overall reaction is substitution of RN for O
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

33. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Imine Derivatives
Addition of amines with an atom containing a lone pair of electrons on the adjacent atom occurs very readily, giving useful, stable imines
For example, hydroxylamine forms oximes and 2,4-dinitrophenylhydrazine readily forms 2,4-dinitrophenylhydrazones
These are usually solids and help in characterizing liquid ketones or aldehydes by melting points
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

34. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Enamine Formation
After addition of R2NH, proton is lost from adjacent carbon
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

35. 19.10 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction
Treatment of an aldehyde or ketone with hydrazine, H2NNH2 and KOH converts the compound to an alkane
Originally carried out at high temperatures but with dimethyl sulfoxide as solvent takes place near room temperature
See Figure for a mechanism
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

36. 19.11 Nucleophilic Addition of Alcohols: Acetal Formation
Two equivalents of ROH in the presence of an acid catalyst add to C=O to yield acetals, R2C(OR)2
These can be called ketals if derived from a ketone
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

37. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Formation of Acetals
Alcohols are weak nucleophiles but acid promotes addition forming the conjugate acid of C=O
Addition yields a hydroxy ether, called a hemiacetal (reversible); further reaction can occur
Protonation of the OH and loss of water leads to an oxonium ion, R2C=OR+ to which a second alcohol adds to form the acetal
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

38. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Uses of Acetals
Acetals can serve as protecting groups for aldehydes and ketones
It is convenient to use a diol, to form a cyclic acetal (the reaction goes even more readily)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

39. 19.12 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction
The sequence converts C=O is to C=C
A phosphorus ylide adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine
The intermediate spontaneously decomposes through a four-membered ring to yield alkene and triphenylphosphine oxide, (Ph)3P=O
Formation of the ylide is shown below
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

40. A Note on the Word “Betaines”
The term “betaines” is an extension from a specific substance (betaine) that has permanent + and – charges (as in a zwitterion) that cannot be neutralized by proton transfers (as in normal amino acids). Webster's Revised Unabridged Dictionary lists: Betaine \Be"ta*ine\, n. [From beta, generic name of the beet.] (Chem.) A nitrogenous base, {C5H11NO2}, produced artificially, and also occurring naturally in beet-root molasses and its residues. The listed pronunciation indicates it has the exact same emphasis as “cocaine”.
Cocaine \Co"ca*ine\, n. (Chem.) A powerful alkaloid, {C17H21NO4}, obtained from the leaves of coca
So – if you say “co-ca-een” (as this dictionary suggests) then you would also say “bee-ta-een”. If you sat “co-cayn” then say “beet-ayn”.
Whatever you say, the “beta” in “betaine” refers to beets and not a letter in the Greek alphabet. There have been a lot of wagers on this over the years. RK
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

41. Uses of the Wittig Reaction
Can be used for monosubstituted, disubstituted, and trisubstituted alkenes but not tetrasubstituted alkenes The reaction yields a pure alkene of known structure
For comparison, addition of CH3MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

42. Mechanism of the Wittig Reaction
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

43. 19.13 The Cannizzaro Reaction: Biological Reductions
The adduct of an aldehyde and OH can transfer hydride ion to another aldehyde C=O resulting in a simultaneous oxidation and reduction (disproportionation)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

44. The Biological Analogue of the Canizzaro Reaction
Enzymes catalyze the reduction of aldehydes and ketones using NADH as the source of the equivalent of H-
The transfer resembles that in the Cannizzaro reaction but the carbonyl of the acceptor is polarized by an acid from the enzyme, lowering the barrier
Enzymes are chiral and the reactions are stereospecific. The stereochemistry depends on the particular enzyme involved.
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

45. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
19.14 Conjugate Nucleophilic Addition to ,b-Unsaturated Aldehydes and Ketones
A nucleophile can add to the C=C double bond of an ,b-unsaturated aldehyde or ketone (conjugate addition, or 1,4 addition)
The initial product is a resonance-stabilized enolate ion, which is then protonated
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

46. Conjugate Addition of Amines
Primary and secondary amines add to , b-unsaturated aldehydes and ketones to yield b-amino aldehydes and ketones
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

47. Conjugate Addition of Alkyl Groups: Organocopper Reactions
Reaction of an , b-unsaturated ketone with a lithium diorganocopper reagent
Diorganocopper (Gilman) reagents from by reaction of 1 equivalent of cuprous iodide and 2 equivalents of organolithium
1, 2, 3 alkyl, aryl and alkenyl groups react but not alkynyl groups
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

48. Mechanism of Alkyl Conjugate Addition
Conjugate nucleophilic addition of a diorganocopper anion, R2Cu, an enone
Transfer of an R group and elimination of a neutral organocopper species, RCu
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

49. 19.15 Biological Nucleophilic Addition Reactions
Example: Many enzyme reactions involve pyridoxal phosphate (PLP), a derivative of vitamin B6, as a co-catalyst
PLP is an aldehyde that readily forms imines from amino groups of substrates, such as amino acids
The imine undergoes a proton shift that leads to the net conversion of the amino group of the substrate into a carbonyl group
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

50. 19.16 Spectroscopy of Aldehydes and Ketones
Infrared Spectroscopy
Aldehydes and ketones show a strong C=O peak 1660 to 1770 cm1
aldehydes show two characteristic C–H absorptions in the 2720 to 2820 cm1 range.
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

51. C=O Peak Position in the IR Spectrum
The precise position of the peak reveals the exact nature of the carbonyl group
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

52. NMR Spectra of Aldehydes
Aldehyde proton signals are at  10 in 1H NMR - distinctive spin–spin coupling with protons on the neighboring carbon, J  3 Hz
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

53. Protons on Carbons Adjacent to C=O
Slightly deshielded and normally absorb near  2.0 to 2.3
Methyl ketones always show a sharp three-proton singlet near  2.1
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

54. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
13C NMR of C=O
C=O signal is at  190 to  215
No other kinds of carbons absorb in this range
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

55. Mass Spectrometry – McLafferty Rearrangement
Aliphatic aldehydes and ketones that have hydrogens on their gamma () carbon atoms rearrange as shown
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

56. Mass Spectroscopy: -Cleavage
Cleavage of the bond between the carbonyl group and the  carbon
Yields a neutral radical and an oxygen-containing cation
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

57. Enantioselective Synthesis
When a chiral product is formed achiral reagents, we get both enantiomers in equal amounts - the transition states are mirror images and are equal in energy
However, if the reaction is subject to catalysis, a chiral catalyst can create a lower energy pathway for one enantiomer - called an enantionselective synthesis
Reaction of benzaldehyde with diethylzinc with a chiral titanium-containing catalyst, gives 97% of the S product and only 3% of the R
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003

58. Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003
Summary
Aldehydes are from oxidative cleavage of alkenes, oxidation of 1° alcohols, or partial reduction of esters
Ketones are from oxidative cleavage of alkenes, oxidation of 2° alcohols, or by addition of diorganocopper reagents to acid chlorides.
Aldehydes and ketones are reduced to yield 1° and 2° alcohols , respectively
Grignard reagents also gives alcohols
Addition of HCN yields cyanohydrins
1° amines add to form imines, and 2° amines yield enamines
Reaction of an aldehyde or ketone with hydrazine and base yields an alkane
Alcohols add to yield acetals
Phosphoranes add to aldehydes and ketones to give alkenes (the Wittig reaction)
-Unsaturated aldehydes and ketones are subject to conjugate addition (1,4 addition)
Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 2003