Chapter 19 Aldehydes and Ketones: Nucleophilic Addition Reactions
Aldehydes and Ketones Aldehydes (RCHO) and ketones (R2CO) are characterized by the carbonyl functional group (C=O) The compounds occur widely in nature as intermediates in metabolism and biosynthesis
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
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 carbaldehyde
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
Ketones with Common Names IUPAC retains well-used but unsystematic names for a few ketones
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 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
Exercise 1
19.2 Preparing Aldehydes and Ketones 1.) Oxidize primary alcohols using pyridinium chlorochromate (PCC) or Dess-Martin Periodinane (DMP) reagent in DCM 2.) Alkenes with a vinylic hydrogen can undergo oxidative cleavage when treated with ozone, yielding aldehydes 3.) Reduce an ester with diisobutylaluminum hydride (DIBAH)
Exercise 2 Preparing Aldehydes 1.) Oxidize primary alcohols using pyridinium chlorochromate (PCC) or Dess-Martin Periodinane (DMP) reagent in DCM 2.) Alkenes with a vinylic hydrogen can undergo oxidative cleavage when treated with ozone, yielding aldehydes 3.) Reduce an ester with diisobutylaluminum hydride (DIBAH)
Preparing Ketones Oxidize a 2° alcohol Many reagents possible: choose for the specific situation (scale, cost, and acid/base sensitivity)
Ketones from Ozonolysis Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted
Aryl Ketones by Acylation Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst
Methyl Ketones by Hydrating Alkynes Hydration of terminal alkynes in the presence of Hg2+ (catalyst: Section 8.4)
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
Hydration of Aldehydes Aldehyde oxidations occur through 1,1-diols (“hydrates”) Formed by reversible nucleophilic addition of water to the carbonyl group Aldehyde hydrate reacts like typical alcohol and is oxidized to a carboxylic acid by usual reagents
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
Exercise 3
19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones Nu- approaches 75° to the plane of C=O and adds to the electrophilic C=O carbon atom A tetrahedral alkoxide ion intermediate is produced Protonation of the alkoxide by addition of acid gives the alcohol product
Nucleophiles Nucleophiles can be negatively charged ( :Nu) or neutral ( :Nu) at the reaction site If Neutral however, it carries a H atom that can be subsequently eliminated
Nucleophilic Addition Nucleophilic additions aldehydes and ketones generally have two variations. 1st pathway – protonated by water or acid to yield alcohol 2nd pathway – carbonyl oxygen is protonated and then eliminated as OH- or water to yield C=Nu double bond
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
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
Reactivity of Aromatic Aldehydes Aromatic aldehydes are less reactive in nucleophilic addition reactions than aliphatic aldehydes Due to electron-donating resonance effect of aromatic ring makes C=O less reactive electrophile than the carbonyl group of an aliphatic aldehyde
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 Position of eq. depends on the structure of carbonyl compound
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
Acid-Catalyzed Addition of Water Under acidic conditions, carbonyl oxygen is protonated first, thus making the C=O group more electrophilic
Addition of H–Y to C=O Reaction of C=O with H-Y, where Y is electronegative, gives an addition product (“adduct”) Rxn mechanism is similar to addition of water to C=O Formation is readily reversible, but generally favours carbonyl reactant
19.6 Nucleophilic Addition of HCN: Cyanohydrin Formation Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)CN 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
Uses of Cyanohydrins The nitrile group (CN) can be reduced with LiAlH4 to yield a primary amine (RCH2NH2) Can be hydrolyzed by hot acid to yield a carboxylic acid
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+.
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
Hydride Addition Convert C=O to CH-OH LiAlH4 and NaBH4 react as donors of hydride ion Protonation after addition yields the alcohol
19.8 Nucleophilic Addition of Amines: Imine and Enamine Formation RNH2 adds to R’2C=O to form imines, R’2C=NR (after loss of HOH) R2NH yields enamines, R2NCR=CR2 (after loss of HOH) (ene + amine = unsaturated amine)
Mechanism of Formation of Imines Primary amine adds to C=O Proton is lost from N and adds to O to yield an amino alcohol (carbinolamine) Protonation of OH converts it 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
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
Enamine Formation After addition of R2NH and loss of water, proton is lost from adjacent carbon
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
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 Acetal formation mech. Similar to the hydration rxn discussed earlier
Mechanism
Mechanism
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)
Uses of Acetals Acetal and hemi-acetals are common in carbohydrate chemistry E.g. glucose is a polyhydroxy aldehyde that undergoes internal nucleophilic addition rxn and exist as a cyclic hemi-acetal
Exercise 4 Show the structure of the acetal you would obtain by acid-catalysed rxn of 2-pentanone with 1,3-propanediol
19.11 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction The sequence converts C=O 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
Mechanism of the Wittig Reaction
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
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
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
Conjugate Addition of Amines Primary and secondary amines add to , b-unsaturated aldehydes and ketones to yield b-amino aldehydes and ketones
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
Mechanism of Alkyl Conjugate Addition: Organocopper Reactions Conjugate nucleophilic addition of a diorganocopper anion, R2Cu, to an enone Transfer of an R group and elimination of a neutral organocopper species, RCu
19.14 Spectroscopy of Aldehydes and Ketones Infrared Spectroscopy Aldehydes and ketones show a strong C=O peak 1660 to 1770 cm1 aldehydes show two characteristic C–H absorptions in the 2720 to 2820 cm1 range.
C=O Peak Position in the IR Spectrum The precise position of the peak reveals the exact nature of the carbonyl group
NMR Spectra of Aldehydes Aldehyde proton signals are near 10 in 1H NMR - distinctive spin–spin coupling with protons on the neighboring carbon, J 3 Hz
13C NMR of C=O C=O signal is at 190 to 215 No other kinds of carbons absorb in this range