Aldehydes & Ketones = Aldehyde = Ketone IR: C = O around 1720 cm -1 C = O 1700 - 1725 cm -1 (lower if R = aromatic) (lower if R = aromatic) C - H around 2700 cm -1 No O - H, C - O or aldehyde C-H NMR: C = O ~ 200 – 215 ppm; lower (190 – 200 ppm) when benzene is adjacent IUPAC Nomenclature: Common names: names of alkyl group(s) + "ketone" or "aldehyde" R O H R O R Aldehydes use alkane name, remove "e", add "al". Number from aldehyde C. For ketones: alkane name - "e" add "one". Position of C=O 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.
Transcript
Aldehydes & Ketones
= Aldehyde = Ketone
IR: C = O around 1720 cm-1 C = O 1700 - 1725 cm-1 (lower if R = aromatic) (lower if R = aromatic) C - H around 2700 cm-1 No O - H, C - O or aldehyde C-H NMR: C = O ~ 200 – 215 ppm; lower (190 – 200 ppm) when benzene is adjacent
IUPAC Nomenclature:
Common names: names of alkyl group(s) + "ketone" or "aldehyde"
R
O
H R
O
R
Aldehydes use alkane name, remove "e", add "al". Number from aldehyde C.
For ketones: alkane name - "e" add "one". Position of C=O 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.
Reactivity: C = O is very polar, electrophilic C
Reactive toward nucleophilic attack at the sp2-hybridized carbonyl carbon
Alkyl groups and H 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 C
Electron-donating R groups make ketones (and aromatic aldehydes) less electrophilic
The larger the R group, the less reactive the ketone
Some examples of important/useful aldehydes and ketones:
Some typical IR spectra:
Preparation of aldehydes & ketones 3 strategies: 1) Oxidation of alcohols
2) Oxidative cleavage of alkenes 3) Reduction of carboxylic acid derivatives
3) Reduction of esters: although LiAlH4 will reduce esters all the way to alcohols, a milder reducing agent will stop at the aldehyde: DIBAH, toluene, -78o C
DIBAH is bulkier & slower, donates only 1 H-
Other reactions producing ketones (review): Friedel-Crafts acylation can be used to produce aryl ketones from benzene
heat, AlCl3
Hydration of alkynes also produces ketones (aldehydes from terminal alkynes)
H3O+
HgSO4
O
O
R
O
Cl
Oxidation reactions of aldehydes & ketones: Review: Strong oxidizers such as Na2Cr2O7 or KMnO4 convert RCHO to RCOOH 1) Oxidation 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+ Ag0 (silver mirror) as the visible change
NaOH NH4OH AgNO3 Ag2O Ag(NH3)2OH
+ 2 Ag(NH3)2OH NH4+ + 2 Ag0 + H2O + 3 NH3
2) Ketone cleavage: Although the ketone group is difficult to oxidize, KMnO4 can slowly cleave the bond between C = O and α-carbon to produce a carboxylic acid: 1. KMnO4, H2O, NaOH 2. H3O+ 3) Oxidation of aldehydes & ketones by peroxyacids: Baeyer-Villiger oxidation Peroxyacids have a very reactive oxygen-oxygen bond; oxygen inserts itself next to C=O: Position of O insertion is determined by mechanism of H or alkyl group migration:
Tendency to migrate: H > 3o alkyl > 2o alkyl, phenyl > 1o alkyl > methyl Predict products:
RC
O
R 1
MCPBA
RC
O
OR1Na2HPO4
H3C
O
CH3
CH3H3C
MCPBA
R
O
H R
O
O
Predominant reaction mechanism of aldehydes & ketones: nucleophilic addition Because the R and H groups of ketones and aldehydes are not leaving groups, substitution reactions do not occur; rather the sp2 C is transformed to sp3 The mechanism begins with nucleophilic attack forming a tetrahedral intermediate: An acid catalyst may be used to activate the carbonyl if the Nu is weak: I. Carbon nucleophiles: Formation of new C - C 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. Review of common carbon nucleophiles: 1) Grignard reagents: Prepared by reaction of alkyl halides with Mg metal:
Ex:
2) Acetylides: Deprotonation of a terminal alkyne
HC C CH2CH3 + NaNH2 C C CH2CH3 3) Cyanide ion: (from NaCN, KCN) 4) Organolithium reagents and organocuprates: CH3Li, R2CuLi
R
O
R+ Nu:-
R
O-
R
Nu
+ H+R
OH
R
Nu
R
O
R + Nu:-R
O
R+ H+
R
OH
R
Nu
H
CH3CH2 + MgBr CH3CH2 MgBr
H3C
O
H+ CH3CH2 MgBr
H+
H3C
OH
H
C C R
C N
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) Reactions with water can lead to formation of gem-diols or hydrates Reactions with alcohols lead to new ether linkages and formation of
hemiacetals, acetals, hemiketals and ketals A. Hydrates: 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: Mechanism:
R
O
H+ R'-OH
R H
OH
OR'
R
O
R+ R'-OH
R R
OH
OR'
aldehyde
ketone
hemiacetal
hemiketal
C. Further reaction of hemiacetals or hemiketals with ROH:
• Acetals or ketals (geminal di-ethers) are produced when a second
equivalent of ROH adds to the central C • These reactions are usually acid-catalyzed & reversible
• Hemiacetal 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)
H3C
O
CH3H3C
CH3
OH
OCH2CH3
H3C
H2C
OH H3C
H2C
OH H3CCH3
OCH2CH3
OCH2CH3
Use of acetal/ketals to protect C=O:
D. Reaction analogous to hydration: cyanohydrin formation Hydrogen cyanide adds to aldehydes & ketones to form cyanohydrins Synthetic utility: the CN group can be further functionalized
Other protic acids (HBr, HCl, H2SO4) do not undergo additions to C = O because the equilibrium constant does not favor the forward reaction.
Et
O
CH3 Et CH3
OH
CNEt CH3
OH
COOH
HCl, NaCN H+, H2O
heat
Et CH3
OH
CH2NH2
1) LiAlH4/THF2) H2O
Mechanism of formation: aldehyde hemiacetal acetal
III. Reactions of nitrogen nucleophiles with aldehydes and ketones A. Formation of the imine group: H2NR C = O C = N – R
Carbonyl Imine Ketones & aldehydes react with ammonia or 1o amine to form a “Schiff base”: 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 Hydrazine & 2,4-dinitrophenylhydrazine:
Identification of unknown aldehydes & ketones: the 2,4-dinitrophenylhydrazone test Imine formation It’s pH-dependent: occurs under moderately acidic conditions (protonation of
the OH makes a good L.G, but not acidic enough to protonate amine) It’s reversible: imines can be hydrolyzed back under acidic conditions
H3C
C O
H3C
:NH2CH3H3C
C N
H3C CH3
H2NHN
NO2
NO2
H2N NH2
Mechanism of imine formation
B. Formation of enamines Reaction of aldehydes & ketones with secondary amines produces enamines (pronounced “een-a-meen”) instead of imines:
Imine Enamine
Mechanism (see previous page) C. Some useful variations Reductive 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:
\ Raney Ni = fine Ni particles with adsorbed H2
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 N2 and protonation gives a methyl or methylene
CH2
C O
H
H3C
HN
CH3
CH3
+ H3C
HC
CH
NCH3
CH3
NCH
R
H3C
R
HC
CH
NR
R
C O:NH3
C NH CH NH2
H2
Raneynickel
RC
O
R 1
H2NNH2
KOHR
H2C R
1+ N2 + H2O
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 O is replaced by a double-bonded C: The most commonly used phosphonium ylide is prepared from SN2 reaction of triphenylphosphine with alkyl halide, followed by deprotonation by a strong base: CH3Li + . . Ph3P: + CH3CH2-Br Ph3P – CH2CH3 Ph3P – CH – CH3 Note: Ph3P = (C6H5)3P A typical Wittig reaction: Elimination of O and P(φ)3 occur through a charged intermediate. -- Common 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.
R
C O
R
R
C CR2
R
C O C CHPh3P
HC
CH3
CH3
+ Ph3P O
Mechanism of Wittig reaction:
How would you prepare each of these alkenes using a Wittig reaction?
V. The effect of resonance on nucleophilic addition: conjugate addition to α,β-unsaturated carbonyl compounds Allylic cations resonate: 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 C, but weaker nucleophiles react more slowly, adding to the conjugated C = C bond. Direct addition to 3-penten-2-one occurs at the carbonyl carbon: Conjugate addition: proceeds by a mechanism involving keto-enol tautomerism and occurs at the β-carbon
-- • LiAlH4, Grignard, RLi form “direct addition” products with ketones, aldehydes • CN-, NR3, Cl-, Br-, R2CuLi, thiols form “conjugate addition” products • NaBH4 adds both ways to give a mixture of products • The weaker nucleophiles also undergo conjugate addition to α,β-unsaturated
