1. Aldehydes and Ketones Structure and properties Nomenclature
Synthesis (some review)
Reactions (some review)
Spectroscopy – mass spec, IR, NMR

2. Structure and properties
Aldehydes and ketones are the simplest carbonyl containing compounds.

3. Structure and properties
The carbonyl carbon and oxygen are sp2 hybridized.

4. Structure and properties
The carbon oxygen double bond is very polarized. The dipole moments of aldehydes and ketones are larger than most alkyl halides and ether.
u = 2.7 D
u = 2.9 D
u = 1.9 D
The high polarization of the carbonyl is due to the electronegativity of oxygen and the separation of charge in the resonance form.

5. Structure and properties
London dispersion
Dipole-Dipole
Hydrogen bonding
The large polarization of the carbonyl functional group produces dipole-dipole interaction between the molecules of aldehydes and ketones.

6. Structure and properties
Hydrogen bonding does not occur between aldehyde and ketone molecules. Hydrogen bonding can occur with other molecules such as water, alcohols and amines.

7. Solubility Soluble in alcohols.
Lone pair of electrons on oxygen of carbonyl can accept a hydrogen bond from O-H or N-H.
Acetone and acetaldehyde are miscible in water. Solubility does decrease with longer chain length (> 4-5 carbons).

8. Naming Ketones (IUPAC)
Replace -e with -one. Indicate the position of the carbonyl with a number. For diones, don’t drop the final –e. Just add –dione.
Number the chain so that carbonyl carbon has the lowest number.
For cyclic ketones the carbonyl carbon is assigned the number 1.
-CHO > RCOR > R-OH > R-NH2 > C=C > C=C

9. Naming Ketones (IUPAC)
3-methyl-2-butanone
3-methylbutan-2-one
3-bromocyclohexanone
4-hydroxy-3-methyl-2-butanone
4-hydroxy-3-methylbutan-2-one

10. Naming Ketones (IUPAC)

11. Common Names for Ketones
Named as alkyl attachments to -C=O.
Use Greek letters instead of numbers. (alpha, beta and gamma)
methyl isopropyl ketone
a-bromoethyl isopropyl ketone

12. Common Ketones to know:
Acetone methyl ethyl ketone (MEK)
Acetophenone propiophenone benzophenone

13. Naming Aldehydes IUPAC: Replace -e with -al.
The aldehyde carbon is number 1.
If -CHO is attached to a ring, use the suffix -carbaldehyde.

14. Examples 3-methylpentanal 2-cyclopentenecarbaldehyde
cyclopent-2-en-1-carbaldehyde

15. Examples

16. Name as Substituent
On a molecule with a higher priority functional group, C=O is oxo- and -CHO is formyl.
Aldehyde priority is higher than ketone.
3-methyl-4-oxopentanal
3-formylbenzoic acid

17. -bromobutyraldehyde
Aldehyde Common Names
Use the common name of the acid.
Drop -ic acid and add -aldehyde.
1 C: formic acid, formaldehyde
2 C’s: acetic acid, acetaldehyde
3 C’s: propionic acid, propionaldehyde
4 C’s: butyric acid, butyraldehyde.
-bromobutyraldehyde
3-bromobutanal

18. Common Aldehyde
Formaldehyde acetaldehyde propionaldehyde butyraldehyde
Benzaldehyde p-tolualdehyde naphthaldehyde

19. Common Aldehyde Trioxane paraformaldehyde
Common forms of aldehydes.
Formalin is a 40% solution of formaldehyde in water.
There are two dry forms of formaldehyde the cyclic trimer trioxane and paraformaldehyde.
Trioxane paraformaldehyde
Heating these materials convert them to formaldehyde.

20. IR Spectroscopy Very strong C=O stretch around 1710 cm-1.
Conjugation lowers C=O frequency to cm-1.
Ring strain raises frequency.
(Cycolpentanone 1745 cm-1, cycolpropanone 1810 cm-1 )
Additional C-H stretch for aldehyde: two absorptions at 2710 cm-1 and 2810 cm-1.

21. NMR Spectroscopy 1H Aldehyde protons are in the δ 9-10 range.
CH3 adjacent to a carbonyl singlet at δ 2.1.
CH2 adjacent to a carbonyl give multiple peaks at δ 2.5.

22. NMR Spectroscopy 13C Carbonyl carbon singlet in the 175-210 ppm range.
Carbons alpha to the carbonyl are in the ppm range.

23. 1H NMR Spectroscopy

24. 13C NMR Spectroscopy

25. Mass Spectroscopy

26. Mass Spectroscopy

27. Mass Spectroscopy

28. Industrial Importance
Acetone and methyl ethyl ketone are important solvents.
Formaldehyde used in polymers like Bakelite.
Flavorings and additives like vanilla, cinnamon, artificial butter.

29. Common aldehydes and Ketones

30. Synthesis Review Oxidation Ozonolysis of alkenes.
2 alcohol + Na2Cr2O7  ketone
1 alcohol + PCC  aldehyde
Ozonolysis of alkenes.

31. Synthesis Review
2 alcohol + Na2Cr2O7  ketone

32. Synthesis Review
1 alcohol + PCC  aldehyde

33. Synthesis Review
Ozonolysis of alkenes.

34. Synthesis Review
Predict the products of the following reactions.

35. Synthesis Review Friedel-Crafts acylation of aromatic rings
Acid chloride/AlCl3 + benzene  ketone
Gatterman-Koch
CO + HCl + AlCl3/CuCl + benzene  benzaldehyde

36. Synthesis Review
Predict the products.

37. Synthesis Review
Predict the products.

38. Synthesis Review Hydration of alkyne
Use HgSO4, H2SO4, H2O : a methyl ketone is obtained with a terminal alkyne.
Use Sia2BH followed by H2O2 in NaOH for aldehyde.

39. Synthesis Review
Hydration of alkyne
Predict the products.

40. Synthesis Review
Hydration of alkyne to an aldehyde

41. Synthesis Using 1,3-Dithiane
Remove H+ with n-butyllithium.
Alkylate with primary alkyl halide, then hydrolyze.
R-X is a primary halide or tosylate.

42. Ketones from 1,3-Dithiane
After the first alkylation, the second H can be removed using BuLi and the resulting anion react with another primary alkyl halide. Giving a ketone upon hydrolyze.

43. Examples of using 1,3-Dithiane

44. Ketones from Carboxylates
Organolithium compounds attack the carbonyl and form a dianion.
Neutralization with aqueous acid produces an unstable hydrate that loses water to form a ketone.
The reaction can be done by first treating with one eq. of LiOH followed by a alkyl/aryl lithium reagent. Consider what is happening in each step (mechanistically how does the reaction work?).

45. Ketones from Carboxylates

46. Ketones from Nitriles
A Grignard or organolithium reagent attacks the nitrile carbon.
The imine salt is then hydrolyzed to form a ketone.

47. Aldehydes from Acid Chlorides
A mild reducing agent can reduce an acid chloride to an aldehyde.
What would happen if you used LAH?
Acid Chlorides are prepared by treating an acid with thionyl chloride (SOCl2).
Show the synthesis of benzaldehyde from toluene.

48. Ketones from Acid Chlorides
Treatment of an acid chloride with lithium dialkylcuprate (R2CuLi) can also be used to synthesize ketones.
Reagent preparation:

49. Ketones from Acid Chlorides
How it the lithium reagent made?

50. Nucleophilic Addition
The addition of a nucleophile to the carbonyl carbon is the most common reaction of aldehydes and ketones.
Note: The carbonyl carbon is an electrophilic center.

51. Nucleophilic Addition
There two general types of addition reactions.
Strong nucleophiles attack the carbonyl carbon, forming an alkoxide ion. The resulting alkoxide is then protonated to give an alcohol. (see previous slide)
Weak nucleophiles attack a carbonyl if it has been protonated (acid conditions). Protonation of the carbonyl increases the reactivity of the carbonyl carbon toward nucleophilic attack. The final step is deprotonation of the nucleophile.

52. Nucleophilic Addition
Strong nucleophile addition.
If the carbonyl carbon becomes a stereo center in the product, both enantiomer are produced.
Weak nucleophile addition.

53. Nucleophilic Addition
Grignard reaction
Grignard reagents add to aldehydes to give secondary alcohols and
ketones to give tertiary alcohols. (one exception: CH2O)

54. Addition of Water hydration
In acid, water is the nucleophile.
In base, hydroxide is the nucleophile.
Aldehydes are more electrophilic since they have fewer e--donating alkyl groups. (more reactive)
Classify the products?

55. Addition of Alcohols
The addition of alcohols to the carbonyl is similar to the addition of water.

56. Mechanism The formation of acetals and ketals is acid catalyzed.
Adding H+ to carbonyl makes it more reactive with weak nucleophile, ROH.
The addition of a single alcohol produces a hemiacetal. Under the acidic reaction conditions water is loss, followed by addition of a second molecule of ROH forming the acetal.
All steps are equilibrium processes (reversible) .

57. Mechanism for Hemiacetal
The acid catalyst protonates the carbonyl.
Alcohol (a weak nucleophile) then adds to the carbonyl.
Loss of H+ gives the hemiacetal.

58. Hemiacetal to Acetal

59. Sugars commonly exist as acetals or hemiacetals.
Cyclic Acetals
Formation of cyclic acetals is used as a way of protecting the carbonyl group from under going nucleophilic attack in subsequent reactions. The protecting group can be remove by treatment with dilute acid.
Cyclic acetals are made by reacting the aldehyde or ketone with a diol
Sugars commonly exist as acetals or hemiacetals.

60. Acetals as Protecting Groups
Hydrolyze easily in acid, stable in base.
Aldehydes more reactive than ketones.

61. Selective Reaction of Ketone
React with strong nucleophile (base).
Remove protective group.

62. Selective Reaction of aldehydes and Ketones
How could the following synthesis be done.

63. Addition of HCN CN- adds to the carbonyl group to give cyanohydrin.
The order of reactivity is: formaldehyde > aldehydes > ketones >> bulky ketones.
The nitrile group can be convert to an acid group by acid hydrolysis.
α-hydroxy acid

64. Schiff base when R is an alkyl group
Formation of Imines
The formation of an imine involves an initial nucleophilic attack by ammonia or a primary amine on the carbonyl carbon. Followed by subsequent loss of a water molecule.
The C=O becomes a C=N-R group where R= H, alkyl or aryl
“imine” also called a
Schiff base when R is an alkyl group

65. Important N-containing derivatives

66. Formation of N derivatives
Loss of water is acid catalyzed, but acid deactivates the nucleophiles.
NH3 + H+  NH4+ (not nucleophilic).
Optimum pH is around 4.5.

67. Wittig Reaction
This reaction involves the nucleophilic addition of a phosphorus ylides to the carbonyl carbon.
The product of a Wittig reaction is an alkene.

68. Phosphorus Ylides ylide
The ylide is prepared by first reacting triphenylphosphine with an unhindered alkyl halide (methyl or primary halide) to form a phosphonium salt.
Treatment with butyllithium then abstracts a hydrogen from the carbon attached to phosphorus to produce the ylide.
ylide

69. Mechanism for Wittig
The negative C on ylide attacks the positive C of carbonyl to form a betaine.
Oxygen combines with phosphine to form the phosphine oxide.

70. Wittig Reaction
Purpose are synthetic route for the preparation of the following compounds.

71. Oxidation of Aldehydes
Aldehydes are easily oxidized to carboxylic acids.

72. Tollens Test
Tollens reagent is prepared by adding ammonia to a AgNO3 solution until the precipitate dissolves.
Addition of Tollens reagent to a solution containing an aldehyde results in the formation of a silver mirror.

73. Reduction Reagents
Sodium borohydride, NaBH4, reduces C=O, but not C=C.
Lithium aluminum hydride, LiAlH4, much stronger, difficult to handle.
Hydrogen gas with catalyst also reduces the C=C bond.

74. Catalytic Hydrogenation
Catalytic hydrogenation is widely used in industry.
Raney nickel, finely divided Ni powder saturated with hydrogen gas.
Pt and Rh also used as catalysts.

75. Deoxygenation Reduction of C=O to CH2 Two methods:
Clemmensen reduction if molecule is stable in hot acid.
Wolff-Kishner reduction if molecule is stable in very strong base.

76. Clemmensen Reduction

77. Wolff-Kisher Reduction
Form hydrazone, then heat with strong base like KOH or potassium t-butoxide.
Use a high-boiling solvent: ethylene glycol, diethylene glycol, or DMSO.