John E. McMurry Paul D. Adams University of Arkansas Chapter 19 Aldehydes and Ketones: Nucleophilic Addition Reactions

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

 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 Why this Chapter?

1. Carboxylic Acids (3 O bonds, 1 OH) 2. Esters (3 O bonds, 1 OR) 3. Amides 4. Nitriles 5. Aldehydes (2 O bonds, 1H) 6. Ketones (2 O bonds) 7. Alcohols (1 O bond, 1 OH) 8. Amines 9. Alkenes, Alkynes 10. Alkanes 11. Ethers 12. Halides The parent will be determined based on the highest priority functional group. Functional Group Priority

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 Aldehydes pentanal5-chloropentanal2-ethylbutanal 3,4-dimethylhexanal 5-chloro-2-methylbenzaldehydem-chloro-benzaldehyde 5-methoxy-2-methylbenzaldehyde

 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 Naming Ketones

 IUPAC retains well-used but unsystematic names for a few ketones Ketones with Common Names

Naming Ketones 2-pentanone5-chloro-2-pentanone 1-chloro-3-pentanone 4-ethylcyclohexanone2-fluoro-5-methyl-4-octanone

Naming Ketones

 The R–C=O as a substituent is an acyl group, used with the suffix -yl from the root of the carboxylic acid  CH 3 CO: acetyl; CHO: formyl; C 6 H 5 CO: 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 (lower priority functional group) Ketones and Aldehydes as Substituents

Ketones/Aldehydes as minor FGs, benzaldehydes

Solubility of Ketones and Aldehydes  Good solvent for alcohols  Lone pair of electrons on oxygen of carbonyl can accept a hydrogen bond from O—H or N—H.  Acetone and acetaldehyde are miscible in water.

 Preparing Aldehydes  Oxidize primary alcohols using PCC (in dichloromethane)  Alkenes with a vinylic hydrogen can undergo oxidative cleavage when treated with ozone, yielding aldehydes  Reduce an ester with diisobutylaluminum hydride (DIBAH)  Like LiAlH Preparing Aldehydes and Ketones

 Oxidize a 2° alcohol (See chapter on alcohols)  Many reagents possible: choose for the specific situation (scale, cost, and acid/base sensitivity) Preparing Ketones

 Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted Ketones from Ozonolysis

 Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl 3 catalyst Aryl Ketones by Acylation

Limitations of FC Acylation  Does not occur on rings with electron-withdrawing substituents or basic amino groups

Mechanism of FC Acylation Not subject to rearrangement like FC alkylation.

 Hydration of terminal alkynes in the presence of Hg 2+ (catalyst: Section 9.4)  Markovnikov addition  Produces enol that tautomerizes to ketone  Works best with terminal alkyne Methyl Ketones by Hydrating Alkynes

 CrO 3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently  Silver oxide, Ag 2 O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes 19.3 Oxidation of Aldehydes

 Ketones oxidize with difficulty  Undergo slow cleavage with hot, alkaline KMnO 4  C–C bond next to C=O is broken to give carboxylic acids  Reaction is practical for cleaving symmetrical ketones Oxidation of Ketones

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

 Nucleophiles can be negatively charged ( :Nu  ) or neutral ( :Nu) at the reaction site  The overall charge on the nucleophilic species is not considered Nucleophiles

 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 Relative Reactivity 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 Electrophilicity of Aldehydes and Ketones

 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 Reactivity of Aromatic Aldehydes

 Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem) diols)  Hyrdation is reversible: a gem diol can eliminate water 19.5 Nucleophilic Addition of H 2 O: Hydration

 Aldehyde hydrate is oxidized to a carboxylic acid by usual reagents for alcohols  Relatively unreactive under neutral conditions, but can be catalyzed by acid or base. Hydration of Aldehydes

 Hydration occurs through the nucleophilic addition mechanism, with water (in acid) or hydroxide (in base) serving as the nucleophile. Acid catalyzed Base catalyzed The hydroxide ion attacks the carbonyl group. Protonation of the intermediate gives the hydrate. Hydration of Carbonyls

 Reaction of C=O with H-Y, where Y is electronegative, gives an addition product (“adduct”)  Formation is readily reversible (unstable alcohol) Addition of H–Y to C=O

 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 -  Addition of CN  to C=O yields a tetrahedral intermediate, which is then protonated  Equilibrium favors adduct 19.6 Nucleophilic Addition of HCN: Cyanohydrin 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 Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation

 Complexation of C=O by Mg 2+, Nucleophilic addition of R: , protonation by dilute acid yields the neutral alcohol  Grignard additions are irreversible because a carbanion is not a leaving group Mechanism of Addition of Grignard Reagents

 Convert C=O to CH-OH  LiAlH 4 and NaBH 4 react as donors of hydride ion  Protonation after addition yields the alcohol Hydride Addition

 RNH 2 adds to R’ 2 C=O to form imines, R’ 2 C=NR (after loss of HOH)  R 2 NH yields enamines, R 2 N  CR=CR 2 (after loss of HOH) (ene + amine = unsaturated amine) 19.8 Nucleophilic Addition of Amines: Imine and Enamine Formation

 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 RNH 2  Optimum pH = 4.5 Mechanism of Formation of Imines

 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 Imine Derivatives

 After addition of R 2 NH and loss of water, proton is lost from adjacent carbon Enamine Formation

 Treatment of an aldehyde or ketone with hydrazine, H 2 NNH 2, and KOH converts the compound to an alkane  Can be conducted near room temperature using dimethyl sulfoxide as solvent  Works well with both alkyl and aryl ketones 19.9 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction

 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, R 2 C=OR + to which a second alcohol adds to form the acetal Nucleophilic Addition of Alcohols: Acetal Formation

Mechanism of Acetal Formation

 Acetals can serve as protecting groups for aldehydes and ketones  Aldehydes more reactive than ketones  It is convenient to use a diol to form a cyclic acetal (the reaction goes even more readily) Uses of Acetals

 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) 3 P=O  Formation of the ylide is shown below Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction

Mechanism of the Wittig Reaction

Product of Wittig Rxn  The Wittig reaction converts the carbonyl group into a new C═C double bond where no bond existed before.  A phosphorus ylide is used as the nucleophile in the reaction.  Ylide usually CH 2 or monosubstituted, but not disubstituted.  Unstabilized ylide tends to favor Z-alkene.

 A nucleophile can add to the C=C double bond of an ,  - unsaturated aldehyde or ketone (conjugate addition, or 1,4 addition)  The initial product is a resonance- stabilized enolate ion, which is then protonated Conjugate Nucleophilic Addition to  -Unsaturated Aldehydes and Ketones

 Primary and secondary amines add to ,  -unsaturated aldehydes and ketones to yield  -amino aldehydes and ketones Conjugate Addition of Amines

 Reaction of an ,  -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 Conjugate Addition of Alkyl Groups: Organocopper Reactions

 Conjugate nucleophilic addition of a diorganocopper anion, R 2 Cu , to an enone  Transfer of an R group and elimination of a neutral organocopper species, RCu Mechanism of Alkyl Conjugate Addition: Organocopper Reactions

 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 Spectroscopy of Aldehydes and Ketones

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

 Aldehyde proton signals are near  10 in 1 H NMR - distinctive spin–spin coupling with protons on the neighboring carbon, J  3 Hz NMR Spectra of Aldehydes

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

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

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