CH 18 ALDEHYDES & KETONES- these two classes of compounds have in common the carbonyl group functionality:

CLASSIFICATION

- aldehydes & ketones are sundered by variant substitution on the carbonyl carbon

STRUCTURE

- the carbonyl carbon employs sp2 hybrid orbitals, resulting in a trigonal planar molecular geometrywith 120o bond angles

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

FG = C O carbonyl group

C OR

H

Aldehyde

or RCHO

R = H or Ar also

C OR

R'

Ketone

or R2CO

R, R' = or or Ar or connected (cyclic) =

HO's = sp2 (C)

EPG = Trigonal planar

MG = Trigonal planar

Bond Angle = 120o

C O

(sp2 HO on C with 2p AO on O)

pi

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

C O

C O

RC's

C O O more electronegative than C ; so polar bond

-I -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 thecarbonyl 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:

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

# C s IUPAC Name Common Name

1 methanal formaldehyde

2 ethanal acetaldehyde

3 propanal propionaldehyde

4 butanal butyraldehyde

5 pentanal valeraldehyde

6 hexanal caproaldehyde

C C C C C C

O

H

123456

IUPAC

Common

EX s

Cyclic aldehydes % Cycloalkanecarbaldehydes

- the aldehyde group is always @ C-1 on the ring (understood; 1 is omitted)

EX s

Aromatic aldehydes % Benzaldehydes

- the aldehyde group is always @ C-1 on the benzene ring

EX s

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

EX s

CHO

cyclopentanecarbaldehyde

CHOCH3O

4-methoxycyclooctanecarbaldehyde

CHO

benzaldehyde

CHO

Br

m-bromobenzaldehyde

CH3CH2 C

O

H

propanalpropionaldehyde

CH3CH2CH2CH2 C

O

H

pentanal

valeraldehyde

CH3 CH

OH

CH2 CHO

3-hydroxybutanal-hydroxybutyraldehyde

CH3CH CH CH2CH2 CHO

hex-4-enal

CH2 C C CH2 CHO

5-phenylpent-3-ynal

CH3 C

O

CH3 CH3CH2CH2 C

O

CH3

2-propanone

acetone

2-pentanone

methyl propyl ketone

CH3 CH

CH3

CH2 C

O

CH2CH36 5 4 3 2 1

5-methyl-3-hexanone

ethyl isobutyl ketone

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 thecarbonyl 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-prefixis used), name ends in ketone (may be two or three words)

EX s

Cyclic ketones % Cycloalkanones

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

EX s

Aromatic ketones % Phenones

EX s

O

F F

2,2-difluorocyclobutanone

O

cyclohexanone

C

O

CH3

acetophenone

methyl phenyl ketone

C

O

CH3HO

p-hydroxyacetophenone

C

O

benzophenone

diphenyl ketone

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

EX s

Carbonyl Substituent Names

- when a more important functional group is present, the carbonyl is named as a substituent prefix

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

Note the order of priority for functional groups studied thus far is:

-CHO > -COR > OH > C=C & C/C > OR, X & R

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

O4

32 1

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

CH3 CH

OCH2CH3

C

O

CH2 CH

CH3

C C H7654321

acyl group

acetylformyl

benzoyl

CR

O

CH3 C

O

H C

O

ethanoylmethanoyl

Ph C

O

C

O

oxo

keto

CH3 C

O

CH2 CH2 C

O

H

4-oxopentanal

-ketovaleraldehyde

PREPARATION

A. Aldehydes

1) Oxidation of Primary Alcohols

Review CH 11-2B

EX.

2) Reduction of Acyl Chlorides

EX.

R CH2 OHOA

R C

H

O

OA = pyridinium chlorochromate (PCC), ...

1o ROH aldehyde

CH2CH2 OH CH2 CHOPCC

R C

O

Cl R C

O

HRA

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

(Rosenmund Reduction)

acyl chloride aldehyde

Cl

O H2

Pd-BaSO4; S H

O

B. Ketones

1) Oxidation of Secondary Alcohols

EX.

2) Electrophilic Aromatic Acylation

AKA: Friedel-Crafts Acylation

EX.

3) Alkyne Hydration

EX.

2o ROH ketone

R CH

R

OH R C

R

OOA

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

OH

CrO3

H+

O

Ar H CR

O

Cl+AlCl3

CAr

O

R

acyl chloride aryl ketonearene

Ar = AG 's only, no DAG 's

AlCl3 = Lewis acid catalyst, others possible

OH

CH3 CH

CH3C

O

ClAlCl3

+ HO C

O

CH

CH3

CH3

R C C HH2O

Hg2+, H+R C

O

CH3

methyl ketonealkyne

Hg2 from HgSO4 ; H from H2SO4

C C H C

O

CH3H2O

Hg2+, H+

4) Lithium Dialkylcuprate Coupling with Acyl Chlorides

- dialkylcuprates are organometallic reagents which provide a milder version of a carbonnucleophile (less reactive than a Grignard reagent)

- lithium dialkylcuprates are prepared from organolithium reagents as follows:

EX.

REACTIONS

- the most common reaction which aldehydes & ketones undergo is:

Nucleophilic Addition Reaction

- 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

R C

O

Cl R'2CuLi+ R C

O

R' + +R'Cu LiCl

acyl chloride lithiumdialkylcuprate

ketone

R, R' = , = or Ar

2 R Li + CuI R2CuLi + LiI Cu Li

C

CR2CuLi =

C

O

Cl C

O

CH3THF

+ (CH3)2CuLi

H Nu + Nu C O HC O

Mechanism

1) Neutral or Basic A

2) Acidic A

- one of these two general mechanisms will operate in every one of the reactions to follow 6 theonly variation will be the nature of the nucleophile itself

- due to steric & electronic factors, aldehydes are more reactive than ketones towards nucleophilicaddition

A. Addition of Water

AKA: Hydration of Aldehydes & Ketones

EX.

H OH+C O HO C OH

carbonyl hydrate

H or OH

aldehyde or ketone

Nu C ONu:H Nu

Nu C O H + Nu:

Nu: = OH-, OR-, H:-, C , CN-, ........

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

C O

catalyticstrongsp2 HO's sp3 HO'ssp3 HO's

Cl3C C

H

OH+

H2O Cl3C C

OH

OH

H

chloral hydrate

+

C O

H

C O H C OH

H Nu:

Nu C O HH Nu C O H + H

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

sp2 HO's sp3 HO'ssp3 HO's

weak

RC'ssp2 HO's

catalyst

B. Addition of Hydrogen Cyanide

Mechanism

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

EX s

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

H CN+C O NC C OH

cyanohydrinaldehyde or ketone

hydrogen cyanide

O

HCNHO CN

H

OHCN

H

HO CN

C

OH

C N

C

OH

COOHH+ or OH-

H2O

RA

C

OH

CH2 NH2

-hydroxy acid

-amino alcohol

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

Mechanism

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

G NH2 + C OH

G N C

aldehyde or ketone

ammonia orderivative

imine orhydrazone

+ H2O

G NH2 = H NH2, R NH2, Ar NH2, H2N NH2, Ar NH NH2, ...

ammonia amines hydrazines

H = buffer soln' about pH 5

EX s

D. Addition of Carbon Nucleophiles

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

1) Grignard Reagents

- organomagnesium halides react with carbonyls to produce all classes of alcohols:

+ C OCH

carbanion aldehyde or ketone

C C OH

alcohol

, ...C

Grignard reagent

metalacetylide

= R MgX, R Li, R3Al, R C C M

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

C

H

O NO2HNH2N

NO2

+ H+

C

H

N NH NO2

NO2

+ H2O

O+ NH3

H+NH

+ H2O

O

+

NH2H+ + H2O

N

+R MgX R C OH

alcohol

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

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

C OR2O

aldehyde or ketone

Grignard reagent

H

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

Mechanism

- recall that the choice of substituents on the carbonyl carbon (H or R) determines the class ofalcohol produced (1o, 2o or 3o)

EX s

+R MgX R C

H

H

OHC OH

H

+R MgX R C

R

R

OHC OR

R

+R MgX R C

H

R

OHC OR

H

aldehyde

formaldehyde

ketone

1111oooo ROH

3333oooo ROH

2222oooo ROH

CHCH3CH2CH3

MgBr + CH3CH2 C

H

OH+Et2O

CH3CH2 CH

CH3

CH

OH

CH2CH3

MgCl

CH3CH2 C

O

CH2CH3 +H+Et2O

CH3CH2 C

OH

CH2CH3

2) Metal Acetylides

- acetylide anions react with carbonyls to produce all classes of alkynyl alcohols

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.

+

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

C O

aldehyde or ketone

HR C C C OHCCR

acetylide anion

alkynol

+ C OH3C

H3C

HC

CH3

CH3OHCCC C

E. Addition of Alcohols

- alcohols react with carbonyls to produce geminal bis-ethers known as acetals:

Mechanism

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

R C

O

H + 2 R'OHH

R C H

OR'

OR'+ H2O

aldehyde alcoholsacetal

R C

O

R" + 2 R'OHH

R C R"

OR'

OR'+ H2O

ketone alcoholsacetal (ketal)

R, R', R" = or = or Ar

H = H2SO4, HCl, ......... (catalyst)

EX s

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

EX.

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 equilibriummust 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 removedby acid hydrolysis (excess water)

- the hemiacetal is usually too unstable to isolate, so an excess of the alcohol is often used toforce the acetal production to completion

- hydroxy carbonyl compounds, on the other hand, can form cyclic hemiacetals, which are stable& isolatable:

EX.

+ H2O

+ H2O

+ 2H

dry

O

+ 2 CH3 OHH

dry

CH3O OCH3

OHCH3CH2CH3 CH

CH3

CH2 C

O

H CH3 CH

CH3

CH2 C

OCH2CH3H

OCH2CH3

+ H2O

O

+H

dryHO OH

OO

(C)n

C

O

O

H(C)n

C

O

OH

hydroxy aldehyde or

hydroxy ketone

cyclic hemiacetal

n = 3 or 4

ring = 5 or 6 member

(stable & isolatable)

HOH

O

4

3

21

HO

H OH

43

21

-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

Mechanism

- metal hydride reagents produce some form of the hydride anion (H:) which then effects anucleophilic 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 carbon-oxygen double bond & not with the carbon-carbon double bond

EX.

C O

aldehyde or ketone

alcohol

RACH OH

(1o or 2o ROH)

RA = NaBH4 , LiAlH4 , ....... (metal hydrides)

or = H2/Ni , H2/Pd , H2/Pt , ........... (catalytic hydrogenation)

NaBH4

H2

Ni OH

O

OH

2) Reduction to Alkanes

AKA: Deoxygenation of Aldehydes & Ketones

Mechanism

- neither reagent involves hydride anion, but the result is the same as any reduction reaction Ltwo hydrogens are added

- the details of the mechanisms will be omitted, but in both cases, the oxygen is made into aleaving 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

C O

aldehyde or ketone

RACH2

methylene

RA = Zn/H (Clemmensen reduction) or N2H4/OH (Wolff-Kishner reduction)

OOO

N2H4

OH

OO

OZn

H

Use in Synthesis

- the Clemmensen reduction provides the key step in a useful preparative route to alkylbenzeneswhich, in many instances, is superior to direct alkylation of the arene

- because of rearrangement & oversubstitution, aromatic alkylation often results in a poor yield(or no yield) of the desired alkylbenzene product

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

EX. Synthesize:

Ar H CR

O

Cl+AlCl3

CAr

O

R

acyl chloride aryl ketonearene

Zn

HCH2Ar R

alkylbenzene

AAAAccccyyyyllllaaaattttiiiioooonnnn////RRRReeeedddduuuuccccttttiiiioooonnnn::::

Ar H CH2R Cl+AlCl3

alkyl chloridearene

CH2Ar R

poor yield of alkylbenzene

because of rrrreeeeaaaarrrrrrrraaaannnnggggeeeemmmmeeeennnntttt & oversubstitution

CH2 CH

CH3

CH3 FROM & R grps

CCCCoooorrrrrrrreeeecccctttt MMMMeeeetttthhhhoooodddd ----

+

IIIInnnnccccoooorrrrrrrreeeecccctttt MMMMeeeetttthhhhoooodddd ----

+

CH2 CH

CH3

CH3Zn

HC

O

CH CH3CH3

AlCl3C

O

Cl CH

CH3

CH3

CH3 CH

CH3

CH2 ClAlCl3

C CH3

CH3

CH3

from R~ via H~ shift

G. Oxidation

- the difference in reactivity is realized in this instance L aldehydes are oxidized; ketones are not

EX s

R C

O

H

ketone

OAR C

O

OH

aldehyde carboxylic acid

R C

O

ROA

NR (no reaction)

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

Tollen'sreagent

H

OCrO3

HOH

O

Tollen's Test -

H

OAg(NH3)2

OH

O

+ Ag

silver mirror