Organic Chemistry

1. Chapter 17:Chapter 17:
Aldehydes and KetonesAldehydes and Ketones
R H
O
Functional Group: CarbonylFunctional Group: Carbonyl
Aldehyde: RCHO,Aldehyde: RCHO,
Ketone: RCOR’,Ketone: RCOR’, R R'
O

2. Some 300 million sperm are released
by the male during ejaculation, while
the female usually produces one large
egg at a time. Only one sperm cell can
fertilize the egg. How does it find it?
Magnification: ~2,500
Sperm are selected for fertilization
by their ability to “smell” a nearby
egg. The 11-carbon aldehyde
bourgeonal, above, activates this
ability, whereas the straight-chain
11-carbon aldehyde, undecanal, shuts
it down.
A little aldehyde at a crucialA little aldehyde at a crucial
moment.......moment.......
O
H

3. NomenclatureNomenclature
The carbonyl group of aldehydes and ketones hasThe carbonyl group of aldehydes and ketones has
prioritypriority over all other polar or functional groupsover all other polar or functional groups
used so far, namelyused so far, namely
RX, ROH, , ,RX, ROH, , , (But not COOH)(But not COOH)
>>In addition:In addition:

4. Systematic NamingSystematic Naming
(IUPAC)(IUPAC)
AldehydesAldehydes
AlkanAlkanee  AlkanAlkanalal. Longest chain starts. Longest chain starts
at carbonyl carbon, which is C1.at carbonyl carbon, which is C1.
ExamplesExamples::
FormFormaldehydealdehyde AcetAcetaldehydealdehyde
IUPAC-accepted common namesIUPAC-accepted common names

5. Cyclic aldehydes have the endingCyclic aldehydes have the ending
-carbaldehyde-carbaldehyde after cycloalkane name.after cycloalkane name.
The carbon attached to -CHO is C1.The carbon attached to -CHO is C1.
Examples:Examples:
TheThe unit as a substituent is calledunit as a substituent is called
formylformyl..
Cis-2-Cis-2-mercaptomercaptocyclo-cyclo-
hexanehexanecarbaldehydecarbaldehyde
CHO
1
2
3
4
SH

6. KetonesKetones
AlkAlkaneane  AlkanAlkanone.one. Longest chainLongest chain
incorporates carbonyl carbon and isincorporates carbonyl carbon and is
numbered from terminus close to C=O.numbered from terminus close to C=O.
Cyclic ketones areCyclic ketones are cycloalkanones;cycloalkanones; CC=O=O
isis C1C1..
Examples:Examples:
CisCis-2-ethenyl-3--2-ethenyl-3-
methylcyclohexanonemethylcyclohexanone
(if racemic) or 2(if racemic) or 2SS,3,3S-.S-.
2-Pentanone
O
H
H

7. An aldehyde containing a ketoneAn aldehyde containing a ketone
C=O is called anC=O is called an oxooxoalkanal.alkanal.
Example:Example:
Substituent name:Substituent name: alkanoylalkanoyl
O
R
O
CH3
acetylacetyl, but, but propanoylpropanoyl
(IUPAC accepted common name)(IUPAC accepted common name)
O
CH3CH2

8. O
O
HO
Complex Aldehydes andComplex Aldehydes and
KetonesKetones
4-Acetylbenzenecarboxylic acid4-Acetylbenzenecarboxylic acid
Br
O
H
O
TransTrans-4-bromo-2-oxo-3-butenal-4-bromo-2-oxo-3-butenal

9. StructureStructure
OrbitalsOrbitals
The carbonyl group contains aThe carbonyl group contains a shortshort,, strongstrong, and very, and very polarpolar bond.bond.
ResonanceResonance
PolarizationPolarization
Molecular structureMolecular structure
EPMEPM
175 kcal mol-1

10. Polarization affects the physicalPolarization affects the physical
constants of aldehydes and ketonesconstants of aldehydes and ketones
-- Boiling points relatively high-- Boiling points relatively high
-- Smaller members (acetaldehyde,-- Smaller members (acetaldehyde,
acetone) are completely miscible withacetone) are completely miscible with
waterwater

11. 11
H NMR: Carbonyl group isH NMR: Carbonyl group is
deshieldingdeshielding
UniquelyUniquely deshieldeddeshielded
by polarization andby polarization and
double bond effectdouble bond effect
J ~ 2Hz

12. 1313
C NMRC NMR
R R'
O
~ 200 ppm~ 200 ppm

13. IRIR υυC OC O
~~
---- = 1690-1750 cm= 1690-1750 cm-1-1
Conjugation reduces , strain increases itConjugation reduces , strain increases itυυCOCO
~~

14. H3C CH3
O
H
11
H NMRH NMR 1313
C NMRC NMR
IRIR

15. UVUV
TheThe ππππ* and n* and nππ**
transitions in acetonetransitions in acetone
λλmaxmax (n(nππ*)*) = 275-295 nm= 275-295 nm
Lone electronLone electron
pairspairs
:: ::

16. SynthesisSynthesis
(A review of Chapter 8)(A review of Chapter 8)
1.1. OxidationOxidation of Alcoholsof Alcohols
PrimaryPrimary  aldehydesaldehydes
SecondarySecondary  ketonesketones
UseUse chromium(VI)chromium(VI) reagentsreagents
Selective: Will not oxidize alkene or alkyneSelective: Will not oxidize alkene or alkyne
units. Especially mild is PCC:units. Especially mild is PCC:
PyridinePyridinePyridinium chlorochromate :Pyridinium chlorochromate : “PCC”“PCC”
NNHH
++
NN
CrOCrO33ClCl
--

17. Avoid water: CausesAvoid water: Causes overoxidationoveroxidation of primary alcoholsof primary alcohols
ExamplesExamples::

18. 2.2. AllylicAllylic Oxidation:Oxidation: MnOMnO22
Selective: Will not attack ordinary alcoholsSelective: Will not attack ordinary alcohols
Allylic H is reactiveAllylic H is reactive

19. 3.3. OzonolysisOzonolysis ofof alkenes:alkenes:
OO33, then reducing agent, then reducing agent
Oxidative cleavage of carbon-carbon doubleOxidative cleavage of carbon-carbon double
bondsbonds

20. 4.4. HydrationHydration of alkynesof alkynes
Hydration of the carbon–carbon triple bond yieldsHydration of the carbon–carbon triple bond yields
enols that tautomerize to carbonyl compoundsenols that tautomerize to carbonyl compounds
MarkovnikovMarkovnikov: Use Hg: Use Hg2+2+
, H, H22O, HO, H++
::
Anti-MarkovnikovAnti-Markovnikov: Use hydroboration-oxidation: Use hydroboration-oxidation

21. 5.5. Friedel-CraftsFriedel-Crafts alkanoylationalkanoylation
((Electrophilic Aromatic Substitution)Electrophilic Aromatic Substitution)

22. ReactionsReactions
E.g., NaBH4,
RLi, RMgX
(H+
)
There are three regions of reactivity inThere are three regions of reactivity in
aldehydes and ketonesaldehydes and ketones
ReviewReview

23. Nucleophilic additions to carbonyls toNucleophilic additions to carbonyls to
give alcoholsgive alcohols
Addition reactions occur withAddition reactions occur with milder nucleophilesmilder nucleophiles, such, such
as water, alcohols, amines, etc. To speed them up,as water, alcohols, amines, etc. To speed them up, acid oracid or
base catalysisbase catalysis is required.is required.

24. Catalyzed IonicCatalyzed Ionic
AdditionsAdditions
Base CatalyzedBase Catalyzed Mechanisms:Mechanisms:
Acid CatalyzedAcid Catalyzed Mechanisms:Mechanisms:
X―Y = H―Nu
X―Y = H―Nu

25. 1.1. Hydration:Hydration: Geminal DiolsGeminal Diols
(Carbonyl Hydrates)(Carbonyl Hydrates)
KK ~ 1~ 1
KK depends on “unhappiness” of C=Odepends on “unhappiness” of C=O
polarization: Electron-withdrawingpolarization: Electron-withdrawing
substituents activate, donors deactivate.substituents activate, donors deactivate.

26. Mechanisms:Mechanisms:

27. ΔΔHH ° =° = -3.09-3.09 kcal molkcal mol-1-1
,, ΔΔSS ° =° = -22.9-22.9 eu,eu,
ΔΔGG ° =° = +3.74+3.74 kcal molkcal mol-1-1
ΔΔHH ° =° = -5.30-5.30 kcal molkcal mol-1-1
,, ΔΔSS ° =° = -17.2-17.2 eu,eu,
ΔΔGG ° =° = -0.18-0.18 kcal molkcal mol-1-1

28. 2. Addition of2. Addition of AlcoholsAlcohols
(Not hemiketal:(Not hemiketal:
IUPAC)IUPAC)
Same as water, initially, to formSame as water, initially, to form hemiacetalshemiacetals
K
K
K varies from
< 1 to > 1, as
with water.
Depends on R.
H+
or HO-
H+
or HO-

29. IntramolecularIntramolecular variantvariant (important for(important for
sugars, Chapter 24):sugars, Chapter 24): Best for 5- andBest for 5- and
6-membered rings.6-membered rings.
Favored by entropyFavored by entropy relativerelative
to intermolecular addition;to intermolecular addition;
ΔΔGG ° =° = ΔΔHH ° - T° - TΔΔSS °°
ΔΔSS ° is° is less negativeless negative forfor
intramolecular reaction.intramolecular reaction.
K >1!

30. We can drive the hemiacetal stepWe can drive the hemiacetal step furtherfurther withwith
more alcohol and withmore alcohol and with HH++
catalysis:catalysis: AcetalsAcetals
Acetals are stable to:Acetals are stable to:
BaseBase
Oxidizing agentsOxidizing agents
Nucleophiles (Grignards,Nucleophiles (Grignards,
alkyllithiums, hydrides)alkyllithiums, hydrides)
Acetals areAcetals are NOTNOT
stable to:stable to:
AcidAcid
(A geminal diether)(A geminal diether)
K >1!
(isolated)

31. Mechanism:Mechanism:
AcetalAcetal

32. Cyclic Acetals:Cyclic Acetals: Protecting GroupsProtecting Groups
o
o
CHCH33OHOH
IntramolecularIntramolecular variantvariant (important for(important for
sugars, Chapter 24).sugars, Chapter 24). Best for 5- and 6-memberedBest for 5- and 6-membered
rings.rings.
HO
O
H
H+
, H2O
Hydrolysis = Deprotection

33. O
OH
O
Br
1.1. HO
OH
2.2. MgMg
3.3.
4.4. HH++
, H, H22OO
O
H

34. This is also a method toThis is also a method to protect diols:protect diols:
O
Br
OH
OH
+
H+
Br
O
O
Mg
BrMg
O
O
O
H+
OH
OH
HO

35. Thioacetals: Stable to acid!Thioacetals: Stable to acid!
Application ofApplication of
thioacetals:thioacetals:
DesulfurizationDesulfurization
Deprotection:Deprotection:
Thioacetalization uses Lewis acid catalysis, e.g., ZnClThioacetalization uses Lewis acid catalysis, e.g., ZnCl22. Again, cyclic. Again, cyclic
version particularly favorable.version particularly favorable.
More applications: Chapter 23.More applications: Chapter 23.

36. 3.3. Amine AdditionsAmine Additions
Example:Example:
Ammonia and primary aminesAmmonia and primary amines
add to the carbonyl functionadd to the carbonyl function
and then dehydrate: Aand then dehydrate: A
““condensationcondensation” reaction.” reaction.

37. Mechanism:Mechanism:
Hemiaminal DehydrationHemiaminal Dehydration
Imine FormationImine Formation
A condensationA condensation
product (-Hproduct (-H22O)O)
LipshutzLipshutz
BBoysBBoys

38. IntramolecularIntramolecular reaction:reaction: Best for 5-Best for 5-
and 6-membered rings.and 6-membered rings.
O
NH2 NCat.Cat. HH++
Teaser: AnTeaser: An 11
H NMRH NMR
spectrum of an iminespectrum of an imine
(downfield region)(downfield region)

39. Special IminesSpecial Imines
+ H+ H22N-OHN-OH
(as H(as H33NN++
-OH Cl-OH Cl--
))
AnAn oximeoxime
++
SemicarbazideSemicarbazide SemicarbazoneSemicarbazone
R R'
O
R R'
N
OH
-H-H22OO
R R'
O
N
H
NH2
O
H2N
R R'
N
H
N
O
NH2
-H-H22OO
R R'
O
++ -H-H22OO
HydrazoneHydrazone
HydroxylamineHydroxylamine

40. Reaction of the carbonyl function withReaction of the carbonyl function with
secondary aminessecondary amines gives hemiaminals ingives hemiaminals in
which normal condensation is notwhich normal condensation is not
possible: No H left on N. Therefore,possible: No H left on N. Therefore,
water loss occurs to the “carbon side”water loss occurs to the “carbon side”
to form anto form an enamineenamine..
EnamineEnamine FormationFormation

41. Mechanism:Mechanism:
Enamines are useful, can be alkylated (Chapter 18-4).Enamines are useful, can be alkylated (Chapter 18-4).

42. Wolff-Kishner ReductionWolff-Kishner Reduction
An Application ofAn Application of HydrazonesHydrazones
Synthesis of a HydrazoneSynthesis of a Hydrazone
Wolff-Kishner ReductionWolff-Kishner Reduction

43. Mechanism:Mechanism: Nitrogen eliminationNitrogen elimination
In practice, the reaction is carried out without isolating
the intermediate hydrazone.
A diazaallylic anion

44. Use in alkylbenzene synthesis:Use in alkylbenzene synthesis:
Br
Br
Br
Br
The Wolff-Kishner reduction is an alternative toThe Wolff-Kishner reduction is an alternative to
the Clemmensen (rough, conc. acid) and thioacetal
desulfurization methods (incompatible with cat. H2-
sensitive groups) of deoxygenating aldehydes and
ketones.

45. 4. Addition of4. Addition of Non-Non-
organometallicorganometallic CarbonCarbon
NucleophilesNucleophiles
a. Cyanide makesa. Cyanide makes cyanohydrinscyanohydrins
To make HCN,
but keep pH
slightly basic
MechanismMechanism
NaNaOHOH
Usefulness: A C-C bond formation and -CN is a versatile functional groupUsefulness: A C-C bond formation and -CN is a versatile functional group

46. b. Theb. The Wittig ReactionWittig Reaction
Phosphonium salt synthesisPhosphonium salt synthesis
Georg Wittig
(1897–1987)
NP 1979
Discovered during an investigation of SDiscovered during an investigation of SNN22
reactions of phosphines with haloalkanes.reactions of phosphines with haloalkanes.
The charge on PThe charge on P
acidifies the adjacentacidifies the adjacent
C-H: DeprotonationC-H: Deprotonation
gives a so-calledgives a so-called ylideylide

47. Other (weaker) bases OK, such as CHOther (weaker) bases OK, such as CH33OO--
, CH, CH33OH, generate the ylide inOH, generate the ylide in
equilibrium concentrations sufficient for the next step: Attack onequilibrium concentrations sufficient for the next step: Attack on
carbonyl carbon and formation of alkenes.carbonyl carbon and formation of alkenes.
NucleophilicNucleophilic Valence shell expandedValence shell expanded
WittigWittig

48. Driving force: Very strong bondDriving force: Very strong bond
CompareCompare::

49. CHCH22=P(C=P(C66HH55))33
Can be made cis or trans selective.Can be made cis or trans selective.
Steroid modificationSteroid modification
O
CH2
H
H
H
O
O
H
H
H
Resonance-stabilized, trans-selective

50. 5. Addition of Hydroxy Groups5. Addition of Hydroxy Groups
Revisited:Revisited: Baeyer-VilligerBaeyer-Villiger
OxidationOxidation
Oxidation of ketones by peroxycarboxylicOxidation of ketones by peroxycarboxylic
acids givesacids gives esters:esters:
Mechanism:Mechanism:
Adolf vonAdolf von
BaeyerBaeyer
(1835-1917)(1835-1917)
NP 1905.NP 1905.
Victor VilligerVictor Villiger
LipshutzLipshutzCarusoCaruso

51. Familiar? Recall: Chapter 9-3Familiar? Recall: Chapter 9-3
And Chapter 12-8And Chapter 12-8
The transition state of the Baeyer-The transition state of the Baeyer-
Villiger oxidation involves migration ofVilliger oxidation involves migration of
R’R’ through a push-pull electronic relay:through a push-pull electronic relay:

52. Examples:Examples:
O
Regioselective!Regioselective!
O
O
O
HH33CCOOHCCOOH
O
O
O
O
OH
OO
Regioselective!Regioselective!