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Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

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1 Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

2 Aldehydes and Ketones Aldehydes (RCHO) and ketones (R2CO) are characterized by the the carbonyl functional group (C=O) The compounds occur widely in nature as intermediates in metabolism and biosynthesis

3 Why this Chapter? Much of organic chemistry involves the chemistry of carbonyl compounds Aldehydes/ketones are intermediates in synthesis of pharmaceutical agents, biological pathways, numerous industrial processes An understanding of their properties is essential

4 19.1 Naming Aldehydes: 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 Ethanal Propanal acetaldehyde Propionaldehyde 2-Ethyl-4-methylpentanal

5 19.1 Naming Aldehydes and Ketones
(Common) Methanal (IUPAC) (Common) Propanone (IUPAC)

6 Naming Aldehydes If the CHO group is attached to a ring, use the suffix carbaldehyde. Cyclohexanecarbaldehyde 2-Naphthalenecarbaldehyde

7 Naming Aldehydes: Common Names end in aldehyde

8 Naming Ketones Replace the terminal -e of the alkane name with –one
Parent chain is the longest one that contains the ketone grp Numbering begins at the end nearer the carbonyl carbon 3-Hexanone (New: Hexan-3-one) 4-Hexen-2-one (New: Hex-4-en-2-one) 2,4-Hexanedione (New: Hexane-2,4-dione)

9 Ketones with Common Names
IUPAC retains well-used but unsystematic names for a few ketones Acetone Acetophenone Benzophenone

10 Ketones and Aldehydes as Substituents
The R–C=O as a substituent is an acyl group, used with the suffix -yl from the root of the carboxylic acid 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

11 Learning Check: Name the following:

12 Solution: Name the following: 2-methyl-3-pentanone
(ethyl isopropyl ketone) 2,6-octanedione 3-phenylpropanal (3-phenylpropionaldehyde) 4-hexenal Trans-2-methylcyclohexanecarbaldehyde Cis-2,5-dimethylcyclohexanone

13 19.2 Preparation of Aldehydes
Oxidation of 1o alcohols with pyridinium chlorochromate PCC Oxidative cleavage of Alkenes with a vinylic hydrogen with ozone

14 Preparation of Aldehydes
Reduction of an ester with diisobutylaluminum hydride (DIBAH)

15 Preparing Ketones Ketones Oxidation of a 2° alcohol
Many reagents possible: Na2Cr2O7, KMnO4, CrO3 choose for the specific situation (scale, cost, and acid/base sensitivity)

16 Ketones from Ozonolysis
Oxidative cleavage of substituted Alkenes with ozone

17 Aryl Ketones by Acylation
Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst

18 Methyl Ketones by Hydrating Alkynes
Hydration of terminal alkynes in the presence of Hg2+ cat

19 Preparation of Ketones
Gilman reaction of an acid chloride

20 Learning Check: Carry out the following transformations:
3-Hexyne  3-Hexanone Benzene  m-Bromoacetophenone Bromobenzene  Acetophenone 1-methylcyclohexene  2-methylcyclohexanone

21 Solution: Carry out the following transformations:
3-Hexyne  3-Hexanone Hg(OAc)2, H3O+ Benzene  m-Bromoacetophenone

22 Solution: Carry out the following transformations:
Bromobenzene  Acetophenone 1-methylcyclohexene  2-methylcyclohexanone

23 19.3 Oxidation of Aldehydes & Ketones
CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids (acidic conditions) Tollens’ reagent Silver oxide, Ag2O, in aqueous ammonia oxidizes aldehydes (basic conditions)

24 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

25 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

26 19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones
Nu- approaches 75° to the plane of C=O and adds to C A tetrahedral alkoxide ion intermediate is produced

27 Nucleophiles

28 Reactions variations

29 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

30 Relative Reactivity of Aldehydes and Ketones
Aldehydes are generally more reactive than ketones in nucleophilic addition reactions Aldehyde C=O is more polarized than ketone C=O Ketone has more electron donation alkyl groups, stabilizing the C=O carbon inductively

31 Reactivity of Aromatic Aldehydes
Aromatic Aldehydes Less reactive in nucleophilic addition reactions than aliphatic aldehydes Electron-donating resonance effect of aromatic ring makes C=O less reactive electrophile than the carbonyl group of an aliphatic aldehyde

32 19.5 Nucleophilic Addition of H2O: Hydration
Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem) diols) Hydration is reversible: a gem diol can eliminate water

33 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

34 Acid-Catalyzed Addition of Water
Protonation of C=O makes it more electrophilic

35 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

36 19.6 Nucleophilic Addition of HCN: Cyanohydrin Formation
Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)CN Addition of HCN is reversible and base-catalyzed, generating nucleophilic cyanide ion, CN- A cyanohydrin

37 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

38 19.7 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 +.

39 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

40 Hydride Addition Convert C=O to CH-OH
LiAlH4 and NaBH4 react as donors of hydride ion Protonation after addition yields the alcohol

41 19.8 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)

42 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

43 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. These are usually solids and help in characterizing liquid ketones or aldehydes by melting points For example, hydroxylamine forms oximes 2,4-dinitrophenylhydrazine readily forms 2,4-dinitrophenylhydrazones

44 Enamine Formation After addition of R2NH, proton is lost from adjacent carbon

45 Imine / Enamine Examples

46 19.9 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

47 The Wolff–Kishner Reaction: Examples

48 19.10 Nucleophilic Addition of Alcohols: Acetal Formation
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

49 Acetal Formation

50 Uses of Acetals Acetals can be protecting groups for aldehydes & ketones Use a diol, to form a cyclic acetal (reaction goes faster)

51 19.11 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction
The sequence converts C=O  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 An ylide

52 Mechanism of the Wittig Reaction

53 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

54 19.12 The Cannizaro Reaction
The adduct of an aldehyde and OH can transfer hydride ion to another aldehyde C=O resulting in a simultaneous oxidation and reduction (disproportionation)

55 19.13 Conjugate Nucleophilic Addition to -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

56 Conjugate Addition of Amines
Primary and secondary amines add to , b-unsaturated aldehydes and ketones to yield b-amino aldehydes and ketones Reversible so more stable product predominates

57 Conjugate Addition of Alkyl Groups: Organocopper Reactions
Reaction of an , b-unsaturated ketone with a lithium diorganocopper reagent Diorganocopper (Gilman) reagents form 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

58 Mechanism of Alkyl Conjugate Addition
Conjugate nucleophilic addition of a diorganocopper anion, R2Cu, to an enone Transfer of an R group and elimination of a neutral organocopper species, RCu

59 19.14 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.

60 C=O Peak Position in the IR Spectrum
The precise position of the peak reveals the exact nature of the carbonyl group

61 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

62 13C NMR of C=O C=O signal is at  190 to  215
No other kinds of carbons absorb in this range

63 Mass Spectrometry – McLafferty Rearrangement
Aliphatic aldehydes and ketones that have hydrogens on their gamma () carbon atoms rearrange as shown

64 Mass Spectroscopy: -Cleavage
Cleavage of the bond between the carbonyl group and the  carbon Yields a neutral radical and an oxygen-containing cation

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