Aldehydes & Ketones. = Aldehyde = Ketone R. NMR: C = O ~ ppm; lower ( ppm) when benzene is adjacent. IUPAC Nomenclature:

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Wilfred Lee
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1 Aldehydes & Ketones = Aldehyde = Ketone I: = around 1720 cm -1 = cm -1 (lower if = aromatic) (lower if = aromatic) - around 2700 cm -1 No -, - or aldehyde - NM: = ~ ppm; lower ( ppm) when benzene is adjacent IUPA Nomenclature: Aldehydes use alkane name, remove "e", add "al". Number from aldehyde. For ketones: alkane name - "e" add "one". Position of = must be numbered. When aldehyde is on a ring: Alkane name + "carbaldehyde" When a substituent = "formyl" When keto group is named as a substituent on a molecule, it's called an "oxo" group. ommon names: names of alkyl group(s) + "ketone" or "aldehyde"

2 eactivity: = is very polar, electrophilic eactive toward nucleophilic attack at the sp 2 -hybridized carbonyl carbon Alkyl groups and are very poor leaving groups: nucleophilic addition is common rather than nucleophilic substitution. Aldehydes are more reactive: less steric hindrance and less stabilization of positive charge on the carbonyl Electron-donating groups make ketones (and aromatic aldehydes) less electrophilic The larger the group, the less reactive the ketone Some examples of important/useful aldehydes and ketones:

3 Some typical I spectra:

4 Preparation of aldehydes & ketones 3 strategies: 1) xidation of alcohols 2) xidative cleavage of alkenes 3) eduction of carboxylic acid derivatives 1) xidations (review) P Na 2 r 2 7 / + 1 o alcohols aldehyde carboxylic acid Na 2 r 2 7 / + 2 o alcohols ketones 2) xidative cleavage: 3 alkenes ketones and/or aldehydes Zn / 3 + 3) eduction of esters: although LiAl 4 will reduce esters all the way to alcohols, a milder reducing agent will stop at the aldehyde: DIBA, toluene, -78 o DIBA is bulkier & slower, donates only 1 - ther reactions producing ketones (review): Friedel-rafts acylation can be used to produce aryl ketones from benzene l heat, All 3 ydration of alkynes also produces ketones (aldehydes from terminal alkynes) 3 + gs 4

5 xidation reactions of aldehydes & ketones: eview: Strong oxidizers such as Na 2 r 2 7 or KMn 4 convert to 1) xidation by Silver: common classification test for aldehydes is the Tollens test Used in olden days to detect sugar in urine of possible diabetics Employs Ag + Ag 0 (silver mirror) as the visible change Na N 4 AgN 3 Ag 2 Ag(N 3 ) Ag(N 3 ) 2 N Ag N 3 2) Ketone cleavage: Although the ketone group is difficult to oxidize, KMn 4 can slowly cleave the bond between = and α-carbon to produce a carboxylic acid: 1. KMn 4, 2, Na ) xidation of aldehydes & ketones by peroxyacids: Baeyer-Villiger oxidation Peroxyacids have a very reactive oxygen-oxygen bond; oxygen inserts itself next to =: 1 MPBA Na 2 P 4 Position of insertion is determined by mechanism of or alkyl group migration: Tendency to migrate: > 3 o alkyl > 2 o alkyl, phenyl > 1 o alkyl > methyl 1 Predict products: MPBA

6 Predominant reaction mechanism of aldehydes & ketones: nucleophilic addition Because the and groups of ketones and aldehydes are not leaving groups, substitution reactions do not occur; rather the sp 2 is transformed to sp 3 The mechanism begins with nucleophilic attack forming a tetrahedral intermediate: + Nu:- - Nu + + An acid catalyst may be used to activate the carbonyl if the Nu is weak: Nu Nu:- Nu I. arbon nucleophiles: Formation of new - bonds Turning carbon atoms into carbanions by deprotonation or reaction with metals is a way to add a new alkyl group to a molecule at the electrophilic carbon. eview of common carbon nucleophiles: 1) Grignard reagents: Prepared by reaction of alkyl halides with Mg metal: Ex: 3 2 Br + Mg 3 2 MgBr MgBr + 3 2) Acetylides: Deprotonation of a terminal alkyne NaN ) yanide N ion: (from NaN, KN) 4) rganolithium reagents and organocuprates: 3 Li, 2 uli

7 II. Addition of water or alcohols to aldehydes and ketones Water and alcohols (weak nucleophiles) can undergo addition to the carbonyl carbon. These reactions take place slowly in water or alcohol (or can be acid-catalyzed) They play an important role in the chemistry of carbohydrates (sugars, starches) eactions with water can lead to formation of gem-diols or hydrates eactions with alcohols lead to new ether linkages and formation of hemiacetals, acetals, hemiketals and ketals A. ydrates: The carbonyl and hydrate forms are in equilibrium in aqueous solution. The more stable the carbonyl group, the smaller percentage existing as hydrate Alkyl groups stabilize the carbonyl but destabilize the hydrate Equilibrium usually favors the carbonyl form B. Formation of hemiacetals and hemiketals: A new ether linkage forms from addition of an alcohol molecule to the carbonyl carbon: aldehyde + '- ' hemiacetal ketone + '- ' hemiketal Mechanism:

8 . Further reaction of hemiacetals or hemiketals with : Acetals or ketals (geminal di-ethers) are produced when a second equivalent of adds to the central These reactions are usually acid-catalyzed & reversible emiacetal linkages are found in monosaccharides (simple sugars); acetal linkages occur in some polysaccharides (sugars & starches) o Example: lactose Mechanism: Addition-Elimination-Addition (See figure next page)

9 Use of acetal/ketals to protect =: D. eaction analogous to hydration: cyanohydrin formation ydrogen cyanide adds to aldehydes & ketones to form cyanohydrins Synthetic utility: the N group can be further functionalized Et 3 l, NaN Et N 3 +, 2 heat Et 3 1) LiAl 4 /TF 2) 2 ther protic acids (Br, l, 2 S 4 ) do not undergo additions to = because the equilibrium constant does not favor the forward reaction. Et 3 2 N 2

10 Mechanism of formation: aldehyde hemiacetal acetal

11 III. eactions of nitrogen nucleophiles with aldehydes and ketones A. Formation of the imine group: = 2 N = N arbonyl Imine Ketones & aldehydes react with ammonia or 1 o amine to form a Schiff base : 3 3 :N 2 3 N Imine chemistry is important in: --amino acid transformation, enzymatic reactions, some colored indicators General mechanism for imine formation: Nucleophilic addition-elimination (See figure next page) Utility: Many reactions of specific amines produce solid derivatives of aldehydes & ketones which are used in chemical classification & derivatization ydrazine & 2,4-dinitrophenylhydrazine: N 2 2 N N 2 2 N N Identification of unknown aldehydes & ketones: the 2,4-dinitrophenylhydrazone test Imine formation It s p-dependent: occurs under moderately acidic conditions (protonation of the makes a good L.G, but not acidic enough to protonate amine) It s reversible: imines can be hydrolyzed back under acidic conditions N 2

12 Mechanism of imine formation

13 B. Formation of enamines eaction of aldehydes & ketones with secondary amines produces enamines (pronounced een-a-meen ) instead of imines: N Imine 3 + N 3 3 Enamine N 3 N 3 Mechanism (see previous page). Some useful variations eductive amination: ketone to amine A protonated imine formed from ammonia is rather unstable and can be reduced by adding hydrogen across the double bond in the presence of a catalyst: :N 3 2 N N 2 aney nickel \ aney Ni = fine Ni particles with adsorbed 2 The Wolff-Kishner reduction: ketones to alkanes 1) The carbonyl is completely reduced by addition of hydrazine forming a hydrazone 2) Base-catalyzed elimination of N 2 and protonation gives a methyl or methylene 1 2 NN 2 K N 2 + 2

14 IV. A more offbeat nucleophile: Phosphonium ylides and the Wittig reaction This reaction is used to replace the carbonyl oxygen of an aldehyde or ketone with an alkenyl group. Basically, a double-bonded is replaced by a double-bonded : 2 The most commonly used phosphonium ylide is prepared from S N 2 reaction of triphenylphosphine with alkyl halide, followed by deprotonation by a strong base: 3 Li +.. Ph 3 P: Br Ph 3 P 2 3 Ph 3 P 3 A typical Wittig reaction: Note: Ph 3 P = ( 6 5 ) 3 P Ph 3 P Ph 3 P Elimination of and P(φ) 3 occur through a charged intermediate. -- ommon way to prepare substituted alkenes -- The Wittig reaction is regioselective: unlike elimination, the double bond will occur at a specific position, alkyl groups will be positioned to avoid steric strain.

15 Mechanism of Wittig reaction: ow would you prepare each of these alkenes using a Wittig reaction?

16 V. The effect of resonance on nucleophilic addition: conjugate addition to α,β-unsaturated carbonyl compounds Allylic cations resonate: 2 The electrophilic site in an α,β-unsaturated carbonyl compound also resonates: keto form enolate form A very strong nucleophile reacts more quickly, adding directly to the carbonyl, but weaker nucleophiles react more slowly, adding to the conjugated = bond. Direct addition to 3-penten-2-one occurs at the carbonyl carbon: 3 3 MgBr onjugate addition: proceeds by a mechanism involving keto-enol tautomerism and occurs at the β-carbon 3 N N 3 3 N N LiAl 4, Grignard, Li form direct addition products with ketones, aldehydes N-, N 3, l-, Br-, 2 uli, thiols form conjugate addition products NaB 4 adds both ways to give a mixture of products The weaker nucleophiles also undergo conjugate addition to α,β-unsaturated carboxylic acids and derivatives

18 I: 1730 cm-1

19 ( 3 ) 2 u - Li + LiAl NN 2 K PhMgBr l (Ph) 3 P- 3 2,4-DNP 2, Pd

pk a Values for Selected Compounds

pk a Values for Selected Compounds Appendix A pk a Values for Selected ompounds ompound pk a ompound pk a I 10 Br 9 2 S 4 9 + 3 3 7.3 3 S 3 7 Br 4.0 4.2 3 4.3 2 N l 7 [( 3 ) 2 ] + 3.8 [ 3 2 ] + 2.5 3 + 1.7 3 S 3 1.2 + 3 N2 0.0 F 3 0.2 l