1 Aldehydes and Ketones: Nucleophilic Addition Reactions

2 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

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) 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

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

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 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

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

8 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) 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) Aryl Ketones by Acylation Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl 3 catalyst (see Section 16.4)

11 Methyl Ketones by Hydrating Alkynes Hydration of terminal alkynes in the presence of Hg 2+ catalyst

Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) Oxidation of Aldehydes and Ketones CrO 3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently Silver oxide, Ag 2 O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes (no acid)

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

14 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

15 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

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

17 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

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) 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

20 Nucleophilic Addition of H 2 O: 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) 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

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

24 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) Nucleophilic Addition of HCN: Cyanohydrin Formation Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)C  N

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) Uses of Cyanohydrins The nitrile group (  C  N) can be reduced with LiAlH 4 to yield a primary amine (RCH 2 NH 2 ) Can be hydrolyzed by hot acid to yield a carboxylic acid

28 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 +.

29 Mechanism of Addition of Grignard Reagents 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

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

31 Nucleophilic Addition of Amines: Imine and Enamine Formation RNH 2 adds to 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)

Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 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 RNH 2 Note that overall reaction is substitution of RN for O

Based on McMurry, Organic Chemistry, Chapter 19, 6th edition, (c) 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

34 Enamine Formation After addition of R 2 NH, proton is lost from adjacent carbon

35 Nucleophilic Addition of Hydrazine: The Wolff– Kishner Reaction Treatment of an aldehyde or ketone with hydrazine, H 2 NNH 2 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

36 Nucleophilic Addition of Alcohols: Acetal Formation Two equivalents of ROH in the presence of an acid catalyst add to C=O to yield acetals, R 2 C(OR) 2 These can be called ketals if derived from a ketone

37 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, R 2 C=OR + to which a second alcohol adds to form the acetal

38 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)

39 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) 3 P=O Formation of the ylide is shown below

40 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 CH 3 MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes

41 Mechanism of the Wittig Reaction

42 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)

43 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.

44 Conjugate Nucleophilic Addition to  - Unsaturated Aldehydes and Ketones 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

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

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

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

48 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

49 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.

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

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

52 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

53 13 C NMR of C=O C=O signal is at  190 to  215 No other kinds of carbons absorb in this range

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

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

56 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

57 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)

6 electron Transition States 58