CH 18

ALDEHYDES & KETONES

FG = C O carbonyl group

- these two classes of compounds have in common the carbonyl group functionality:

CLASSIFICATION
- aldehydes & ketones are sundered by variant substitution on the carbonyl carbon
R H C O or RCHO R R' C O Ketone R, R' = or = or Ar or connected (cyclic) or R2CO

Aldehyde R = H or Ar also

STRUCTURE
- the carbonyl carbon employs sp2 hybrid orbitals, resulting in a trigonal planar molecular geometry with 120o bond angles
HO's = sp2 (C) EPG = Trigonal planar MG = Trigonal planar Bond Angle = 120o (sp2 HO on C with 2p AO on O)

O
(2p AO on C with 2p AO with O)

- the carbonyl bond is polar (-I effect) and resonance stabilized (-R effect), rendering the carbonyl carbon a strong electrophile & making it susceptible to nucleophilic attack

C O

O more electronegative than C ; so polar bond

C O

C O

-I
RC's

-R

NOMENCLATURE
Aldehydes
IUPAC Nomenclature Alkanals

- the aldehyde is the highest priority functional group encountered thus far, so: - the aldehyde group gets the lowest number % CHO is always @ C-1 (understood; 1 is omitted) - the aldehyde suffix (al) ends the name % the longest continuous carbon chain containing the carbonyl carbon is named by changing: alkane ! alkanal

Common Naming

Prefixaldehydes

- the prefix is source-derived & the name is one word, ending in aldehyde - Greek letters are used to designate substituent positions on the main chain:
Common

O
1

C C C C C C H
6 5 4 3 2

IUPAC

- the IUPAC & common names of the first six simple aldehydes are:

# C s 1 2 3 4 5 6

IUPAC Name methanal ethanal propanal butanal pentanal hexanal

Common Name formaldehyde acetaldehyde propionaldehyde butyraldehyde valeraldehyde caproaldehyde

EX s
O CH3CH2 C H propanal propionaldehyde CH3CH2CH2CH2 pentanal valeraldehyde O C H CH3 OH CH CH2 CHO 3-hydroxybutanal -hydroxybutyraldehyde

Cyclic aldehydes % Cycloalkanecarbaldehydes - the aldehyde group is always @ C-1 on the ring (understood; 1 is omitted) EX s
CHO CH3O CHO

cyclopentanecarbaldehyde

4-methoxycyclooctanecarbaldehyde

Aromatic aldehydes % Benzaldehydes - the aldehyde group is always @ C-1 on the benzene ring EX s
CHO CHO

Br benzaldehyde

m-bromobenzaldehyde

Unsaturated aldehydes % Alk-enals (C=C) & Alk-ynals (C/C) EX s

CH3CH CH CH2CH2 CHO CH2 C C CH2 CHO

hex-4-enal

5-phenylpent-3-ynal

Ketones
IUPAC Nomenclature Alkanones

- the ketone carbonyl carbon must be numbered (lowest possible number) - the ketone suffix (one) ends the name % the longest continuous carbon chain containing the carbonyl carbon is named by changing: alkane ! alkanone

Common Naming

Alkyl ketones

- both groups on the carbonyl carbon are named (if the groups are the same (R = R); a di-prefix is used), name ends in ketone (may be two or three words)

EX s

O CH3 C CH3 2-propanone acetone

O CH3CH2CH2 C 2-pentanone methyl propyl ketone CH3 CH3 CH CH2

6 5

O CH3
4

C
3

CH2CH3
2 1

5-methyl-3-hexanone ethyl isobutyl ketone

Cyclic ketones % Cycloalkanones - the ketone carbonyl can be a ring carbon @ C-1 in the ring (understood; 1 is omitted)

EX s

F cyclohexanone

2,2-difluorocyclobutanone

Aromatic ketones % Phenones

EX s

O C CH3 HO

O C CH3

O C benzophenone diphenyl ketone

acetophenone methyl phenyl ketone

p-hydroxyacetophenone

Unsaturated ketones % Alk-en-ones (C=C) & Alk-yn-ones (C/C)

O
3 2 1 1 2

EX s

O
3

CH3 CH C

CH2 CH C CH3

C H

OCH2CH3 (E)-4-phenylbut-3-en-2-one

2-ethoxy-5-methylhept-6-yn-3-one

Carbonyl Substituent Names - when a more important functional group is present, the carbonyl is named as a substituent prefix
O R C acyl group O H C methanoyl formyl CH3 O C Ph O C O C oxo keto

ethanoyl acetyl

benzoyl

EX. aldehyde FG more important than ketone FG; so ketone named as substituent prefix
O CH3 O

C CH2 CH2 C H 4-oxopentanal

-ketovaleraldehyde

Note the order of priority for functional groups studied thus far is: -CHO > -COR > OH > C=C & C/C > OR, X & R

PREPARATION
A. Aldehydes
1) Oxidation of Primary Alcohols
OA H R C O aldehyde

CH2

OH

1o ROH

OA = pyridinium chlorochromate (PCC), ...

Review CH 11-2B EX.

CH2CH2 OH PCC CH2 CHO

2) Reduction of Acyl Chlorides

O R C Cl O R C H

RA

acyl chloride

aldehyde

RA = LiAlH(O-t-Bu)3 (hydride); H2/Pd-BaSO4; S (catalytic); ....... (Rosenmund Reduction)

EX.
O Cl H2 Pd-BaSO4; S O H

B. Ketones
1) Oxidation of Secondary Alcohols
R
o

CH OH R

OA

C O R

2 ROH

ketone

OA = CrO3/H+, Na2Cr2O7/H2SO4, KMnO4.....

EX.

OH CrO3 H+

2) Electrophilic Aromatic Acylation AKA: Friedel-Crafts Acylation

O Ar H + R C Cl AlCl3 O Ar C R

arene

acyl chloride

aryl ketone

Ar = AG 's only, no DAG 's AlCl3 = Lewis acid catalyst, others possible

EX.

OH CH3 + CH3 CH C Cl O AlCl3 O HO C CH CH3 CH3

3) Alkyne Hydration
R C C H H2O Hg2+, H+ O R C CH3

alkyne

methyl ketone

Hg2

from HgSO4 ;

from H2SO4

EX.
C C H H2O Hg2+, H+ O C CH3

4) Lithium Dialkylcuprate Coupling with Acyl Chlorides - dialkylcuprates are organometallic reagents which provide a milder version of a carbon nucleophile (less reactive than a Grignard reagent)
O R C Cl + R'2CuLi lithium dialkylcuprate R O C R' + R'Cu + LiCl

acyl chloride

ketone

R, R' = , = or Ar

- lithium dialkylcuprates are prepared from organolithium reagents as follows:

C 2R Li + CuI R2CuLi + LiI R2CuLi = C Cu Li

EX.

O C Cl + (CH3)2CuLi THF

O C CH3

REACTIONS
- the most common reaction which aldehydes & ketones undergo is: Nucleophilic Addition Reaction
H Nu + C O Nu C O H

- the reaction occurs under two types of conditions & the mechanism is medium-dependent: - neutral or basic conditions are characterized by a strong nucleophile - acidic condtions are characterized by a weak nucleophile

Mechanism 1) Neutral or Basic A

H Nu Nu: strong sp2 HO's sp3 HO's sp3 HO's C O Nu C O Nu C O H + Nu: catalytic

Nu: = OH-, OR-, H:-,

, CN-, ........

H Nu = H2O, ROH, NH3, H+ (added later), .......

2) Acidic A
H C O sp2 HO's C O H RC's sp2 HO's H Nu: weak C OH H Nu C O H Nu C O H + H catalyst

sp3 HO's

sp3 HO's

H Nu = H2O, ROH, H NH2, ...

- one of these two general mechanisms will operate in every one of the reactions to follow 6 the only variation will be the nature of the nucleophile itself - due to steric & electronic factors, aldehydes are more reactive than ketones towards nucleophilic addition

A. Addition of Water
AKA: Hydration of Aldehydes & Ketones
H or OH C O aldehyde or ketone + H OH HO C OH carbonyl hydrate

EX.

H Cl3C C O + H2O

H+

OH Cl3C C H OH chloral hydrate

B. Addition of Hydrogen Cyanide

C O aldehyde or ketone + H CN hydrogen cyanide NC C OH cyanohydrin

Mechanism - hydrogen cyanide, a weak acid, produces a catalytic amount of the nucleophilic cyanide anion:

EX s
O O H HCN HO CN H HCN HO CN

- cyanohydrins are useful synthetic intermediates 6 they can be hydrolyzed or reduced to compounds with cosmetic & pharmaceutical potential

OH H or OH OH C C N
+ -

C COOH

-hydroxy acid

H2 O RA OH C -amino alcohol CH2 NH2

C. Addition of Nitrogen Nucleophiles

- ammonia or one of its derivatives reacts with a carbonyl compound which, after dehydration, produces a carbon-nitrogen double bonded molecule
G NH2 + ammonia or derivative C O aldehyde or ketone H G N C imine or hydrazone + H2 O

G NH2 = H NH2, R ammonia

NH2, Ar amines

NH2, H2N NH2, Ar

NH NH2, ...

hydrazines

H = buffer soln' about pH 5

Mechanism - nucleophilic addition reaction (NAR) of H-NHG to produce a carbinolamine intermediate, followed by acid-catalyzed dehydration to the imine or hydrazone

EX s

O + NH3

H+

NH + H2O

O +

NH2

H+

N + H2 O

H C O + H2N HN

NO2 NO2 H
+

H C N NH

NO2 NO2 + H2O

D. Addition of Carbon Nucleophiles

- carbanions (R:) and related organometallic species react with carbonyl carbons to produce carbon-carbon bonds 6 a most useful synthetic methodology
H

C O aldehyde or ketone Li, R3Al,

C OH

carbanion

alcohol

= R MgX, R Grignard reagent

R C

M , ...

metal acetylide

H = H2O , NH4 , ROH , ........

1) Grignard Reagents - organomagnesium halides react with carbonyls to produce all classes of alcohols:
R MgX Grignard reagent + C O aldehyde or ketone R2O H R C OH alcohol

R = 1o, 2o, 3o, Ar, ....... H = H2O, NH4+, ........ also

R2O = Et2O, THF, ..........

Mechanism

- recall that the choice of substituents on the carbonyl carbon (H or R) determines the class of alcohol produced (1o, 2o or 3o)
R MgX + H H C O H R
o

C OH H

formaldehyde R H C O

1 ROH R R
o

R MgX

C OH H

aldehyde R R C O

2 ROH R R
o

R MgX

C OH R

ketone

3 ROH

EX s
H CH3CH2 CH MgBr CH3 + CH3CH2 C O Et2O H+ CH3CH2 CH3 OH CH CH CH2CH3

O CH3CH2 C CH2CH3 +

MgCl Et2O

H+

OH CH3CH2 C CH2CH3

2) Metal Acetylides - acetylide anions react with carbonyls to produce all classes of alkynyl alcohols
H

C O aldehyde or ketone

C OH

acetylide anion

alkynol

R = 1o, 2o, 3o, Ar, .......

H = H2O, NH4+, ........ also

Mechanism

- as mentioned previously for the Grignard reaction, the choice of substituents on the carbonyl carbon (H or R) determines the class of alkynol produced (1o, 2o or 3o)

EX.
C C + H3C H3C C O H CH3 C C C OH CH3

E. Addition of Alcohols
- alcohols react with carbonyls to produce geminal bis-ethers known as acetals:
O R C H + 2 R'OH alcohols H OR' R C H OR' acetal + H2 O

aldehyde

O R C R" + 2 R'OH alcohols

OR' R C R" OR' acetal (ketal) + H2 O

ketone

R, R', R" = or = or Ar H = H2SO4, HCl, ......... (catalyst)

Mechanism - nucleophilic addition reaction (NAR) of RO-H to produce a hemiacetal intermediate, followed by substitution of the OH by OR to produce the acetal

EX s
O CH3 CH CH2 C H + 2 CH3CH2 OH CH3 H dry CH3 OCH2CH3 CH3 CH CH2 C H OCH2CH3 + H2O

O + 2 CH3 OH H dry

CH3O

OCH3 + H2O

- vicinal diols, commonly known as glycols, produce cyclic acetals: EX.

O + HO OH H dry O O + H 2O

Reaction Features - acid catalysis is required for acetal formation (or no reaction occurs) - the reaction is highly reversible 6 to obtain a reasonable yield of acetal product, the equilibrium must be forced to the right by excluding water initially & as it forms during the reaction - the reversible reaction makes acetals useful as protecting groups 6 acetals are easily removed by acid hydrolysis (excess water) - the hemiacetal is usually too unstable to isolate, so an excess of the alcohol is often used to force the acetal production to completion - hydroxy carbonyl compounds, on the other hand, can form cyclic hemiacetals, which are stable & isolatable:
O C (C)n O H (C)n O cyclic hemiacetal (stable & isolatable) OH C n = 3 or 4 ring = 5 or 6 member

hydroxy aldehyde or hydroxy ketone

EX.
O HO
4 3 1 2

H H

3 2

O H
1

OH

-hydroxybutyraldehyde

F. Addition of Hydride
AKA: Reduction of Aldehydes & Ketones - recall the practical definition of reduction % adding two hydrogens - in this case, one of those hydrogens is the nucleophilic hydride anion (H:) - two functional group class products are obtainable from hydride addition to a carbonyl:

1) Reduction to Alcohols
C O aldehyde or ketone RA CH OH alcohol (1o or 2o ROH)

RA = NaBH4 , LiAlH4 , ....... (metal hydrides) or = H2/Ni , H2/Pd , H2/Pt , ........... (catalytic hydrogenation)

Mechanism - metal hydride reagents produce some form of the hydride anion (H:) which then effects a nucleophilic addition reaction - a protic solvent or acid added in a later step provides the second hydrogen (as H+)

- the metal hydride reagent is more functional group-specific, reacting only with the carbonoxygen double bond & not with the carbon-carbon double bond
NaBH4 OH

EX.
O H2 Ni

OH

2) Reduction to Alkanes AKA: Deoxygenation of Aldehydes & Ketones

RA

C O aldehyde or ketone

CH2 methylene

RA = Zn/H (Clemmensen reduction) or N 2H4/OH

(Wolff-Kishner reduction)

Mechanism - neither reagent involves hydride anion, but the result is the same as any reduction reaction L two hydrogens are added - the details of the mechanisms will be omitted, but in both cases, the oxygen is made into a leaving group & subsequently substituted for by the second hydrogen

- note L the reagents are complementary A one is strongly acidic & the other strongly basic - this allows a choice of conditions if other acid- or base-sensitive functional groups are present

EX s
O O O N2H4 OH O O

O Zn H

Use in Synthesis - the Clemmensen reduction provides the key step in a useful preparative route to alkylbenzenes which, in many instances, is superior to direct alkylation of the arene
Acylation/Reduction: O Ar H + R C Cl AlCl3 O Ar C R Zn H

Ar CH2 R alkylbenzene

arene

acyl chloride

aryl ketone

- because of rearrangement & oversubstitution, aromatic alkylation often results in a poor yield (or no yield) of the desired alkylbenzene product
Ar H + R CH2 Cl alkyl chloride AlCl3 Ar CH2 R poor yield of alkylbenzene

arene

bec aus e of rearrangement & oversubstitution

- the two-step acylation/reduction sequence is thus the method of choice when attempting to prepare arenes with primary alkyl groups

EX. Synthesize:

CH2 CH CH3 CH3

FROM

& R grps

Correct Method Zn H O C CH CH3 CH3 AlCl3 O + Cl C CH CH3 CH3

CH2 CH CH3 CH3

Incorrect Method CH3 C CH3 CH3 from R~ via H~ shift

CH3 CH CH2 Cl CH3

AlCl3

G. Oxidation
- the difference in reactivity is realized in this instance L aldehydes are oxidized; ketones are not
O R C H OA O R C OH

aldehyde O R C R ketone

carboxylic acid

OA

NR (no reaction)

OA = CrO3/H+, Na2Cr2O7/H2SO4, KMnO4 , Ag(NH3)2 , Cu2+ complexes ,........... Tollen's reagent

EX s
O H O OH

CrO3 H

Tollen's Test O H Ag(NH3)2 O OH + Ag

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