1. Puan Rozaini Abdullah School of Bioprocess Engineering

2. Objectives/Study Questions  1.What is the general structure for an aldehyde? A ketone?  2.How are the common names of aldehydes and ketones determined? How are aldehydes and ketones named using IUPAC nomenclature?  3.Why are the boiling points of aldehydes and ketones higher than those of ethers and alkanes of similar molar masses, but lower than those of comparable alcohols?

3. Objectives/Study Questions  4.How do the solubilities of aldehydes and ketones of four carbons or less compare to the solubilities of comparable alkanes and alcohols in water?  5.How are aldehydes and ketones prepared?  6.What typical reactions take place with aldehydes and ketones?  7.What are some common aldehydes and ketones and their uses?

4. Aldehydes  Comes from alcohol dehydrogenation  Obtained by removing of a hydrogen from an alcohol

5. 5 Naming Aldehydes  IUPAC: Replace -e with -al.  The aldehyde carbon is number 1.

6. 6 Nomenclature of Aldehydes

7. 7 If the aldehyde group is attached to a ring, the aldehyde is naming by adding “carbaldehyde” to name the cyclic compound.

8. 8 If a compound has two functional groups, the one with the lower priority is indicated by its prefix:

9. 9 Nomenclature of Ketones The carbonyl is assumed to be at the 1-position in cyclic ketones:

10. 10 If a ketone has a second functional group of higher priority… A few ketones have common names:

11. Common Carbonyl Compounds  Formaldehyde Manufactured from methanol Used in many polymers  Acetaldehyde Prepared from ethyl alcohol Formed in the detoxification of alcohol in the liver  Acetone Formed in the human body as a by-product of lipid metabolism Excreted in the urine  Hormones Steroid hormones Progesterone/Testosterone

12. Which is the systematic name for the following compound? A.3-methyl-4-oxopentanal B.3-methyl-2-oxopentanal C.3-methyl-2-oxo-5-pentanal D.3-methyl-5-oxo-2-pentanone E.3-methylpentan-5-one-1-al Learning Check:

13. Which is the systematic name for the following compound? A.3-methyl-4-oxopentanal B.3-methyl-2-oxopentanal C.3-methyl-2-oxo-5-pentanal D.3-methyl-5-oxo-2-pentanone E.3-methylpentan-5-one-1-al The aldehyde group has higher priority than the keto group and is assigned the 1 position.

14. Learning Check:  Name the following: 14

15. Solution:  Name the following: 15 2-methyl-3-pentanone (ethyl isopropyl ketone) 3-phenylpropanal (3-phenylpropionaldehyde) 2,6-octanedione Trans-2-methylcyclohexanecarbaldehyde 4-hexenal Cis-2,5-dimethylcyclohexanone

16. Physical Properties of Aldehydes and Ketones  Carbon-oxygen double bond is very polar Affects boiling points More than ethers (C-O bonds) Less than alcohols (C-OH bonds)  Odors Low aldehydes very pungent High aldehydes pleasant odors (perfumes)  Solubility Similar to alcohols and ethers Soluble up to about 4 carbons Insoluble after that

17. Chapter 1817 Solubility  Good solvent for 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.

18. The Relative Reactivities Of Carbonyl Compounds Base on polarity of the carbonyl group results from oxygen being more electronegative than carbon. The partial positive charge on the carbonyl carbon causes that carbon to be attacked by nucleophiles:

19. 19 An aldehyde has a greater partial positive charge on its carbonyl carbon than does a ketone because a hydrogen is more electron than an alkyl group. The Relative Reactivities Of Carbonyl Compounds

20. Relative Reactivity of Aldehydes and Ketones  Aldehydes are generally more reactive than ketones in nucleophilic addition reactions The transition state for addition is less crowded and lower in energy for an aldehyde (a) than for a ketone (b) Aldehydes have one large substituent bonded to the C=O: ketones have two 20 Aldehyde Ketone

21. 21 Why are aldehyde and ketone at the middle? Carbonyl compounds other than aldehydes & ketones have a lone pair on an atom (:Y) attach to the carbonyl group that can be shared with the carbonyl carbon by resonance electron donation. This is makes the carbonyl carbon less electron deficiency and therefore less reactive.

22. Which is the correct order of decreasing reactivity toward nucleophilic attack? A.1 > 2 > 3 > 4 > 5 B.1 > 2 > 5 > 4 > 3 C.1 > 5 > 2 > 4 > 3 D.2 > 5 > 1 > 3 > 4 E.5 > 2 > 1 > 3 > 4 1.Acyl halide 2.Aldehyde 3.Carboxylate ion 4.Carboxylic acid 5.Ketone Learning Check:

23. Which is the correct order of decreasing reactivity toward nucleophilic attack? A.1 > 2 > 3 > 4 > 5 B.1 > 2 > 5 > 4 > 3 C.1 > 5 > 2 > 4 > 3 D.2 > 5 > 1 > 3 > 4 E.5 > 2 > 1 > 3 > 4 1.Acyl halide 2.Aldehyde 3.Carboxylate ion 4.Carboxylic acid 5.Ketone Acid halides are the most reactive carboxylic acid derivative. Aldehydes are more reactive than ketones since they are less hindered and have only one donor group attached to the carbonyl.

24. Preparation of Aldehydes  Oxidation Leads to carboxylic acid unless care is taken 1° alcohols

25. Preparation of Ketones  Oxidation of a 2° alcohol  Utilizes chromium compounds and sulfuric acid

26. What is formed when aldehydes are oxidised? It depends on whether the reaction is done under acidic or alkaline conditions. Under acidic conditions, the aldehyde is oxidised to a carboxylic acid. Under alkaline conditions, this couldn't form because it would react with the alkali. A salt is formed instead.

27. Oxidation of Aldehyde Aldehydes, RCHO, can be oxidised to carboxylic acids, RCO 2 H. Ketones are not oxidised under these conditions as they lack the critical H for the elimination to occur. The reactive species in the oxidation is the hydrate formed when the aldehyde reacts with the water.aldehyde reacts with the water

28. OXIDATION OF ALDEHYDES Part 1: Formation of the hydrate occurs first. Part 2: Now we essentially have an alcohol which reacts with the chromium species to form a chromate ester. Part 3: A base (here a water molecule) abstracts a proton from the chromate ester, the C=O forms and a Cr species leaves. This is really an E2 elimination. reaction. Note the importance of the original aldehyde H... if its' missing, no oxidation can occur.

29. Oxidation of Ketone: Baeyer–Villiger oxidation KetonePeroxy acidEsterCarboxylic acid One of oxygen from the proxy acid is inserted between carbonyl group. One of the oxygen group is attach to the carbon of the ketone to give an ester.

30. Baeyer–Villiger Oxidation Step 1: An acid/base reaction. Protonation of the carbonyl activates it while creating a more reactive nucleophile, the percarboxylate. Step 2: Now the nucleophilic O attacks the carbonyl C with the electrons from the p bond going to the positive O. Step 3: Electrons from the O come back (this reforms the p bond of the C=O) and we migrate the C-C electrons to form a new C- O bond displacing the carboxylate as a leaving group. Step 4: Finally an acid/base reaction reveals the C=O and therefore the ester product.

31. Typical reagents are aqueous Cr (VI) species:

32. 32 The Tollens reagent oxidizes only aldehydes: Tollent Test: Add a small amount of aldehyde in a test tube, inside the test tube The sample becomes coated with a shiny mirror of metallic silver. If the mirror not formed, we can conclude that the compound does not contain any aldehyde group.

33. Reduction of Aldehyde & Ketone In general terms, reduction of an aldehyde leads to a primary alcohol. Reduction of a ketone leads to a secondary alcohol.

34.  Aldehydes and ketones are most readily reduced with hydride reagents.  The reducing agents LiAlH 4 and NaBH 4 act as a source of 4H - (hydride ion).  Overall 2 H atoms are added across the C=O to give H-C-O-H.  Hydride reacts with the carbonyl group, C=O, in aldehydes or ketones to give alcohols.  The substituents on the carbonyl dictate the nature of the product alcohol.  Reduction of methanal (formaldehyde) gives methanol.  Reduction of other aldehydes gives primary alcohols.  Reduction of ketones gives secondary alcohols.  The acidic work-up converts an intermediate metal alkoxide salt into the desired alcohol via a simple acid base reaction.

35. NUCLEOPHILIC ADDITION OF LiAlH 4 TO AN ALDEHYDE Step 1: The nucleophilic H in the hydride reagent adds to the electrophilic C in the polar carbonyl group in the aldehyde, electrons from the C=O move to the O creating an intermediate metal alkoxide complex. (note that all 4 of the H atoms can react) Step 2: This is the work-up step, a simple acid/base reaction. Protonation of the alkoxide oxygen creates the primary alcohol product from the intermediate complex.

36. Reduction of Aldehyde & Ketone by Sodium Borohydrate  Sodium borohydrate is a milder reducing agent and shows considerable selectivity and, although it reduces acid chlorides, aldehydes and ketones rapidly.  It is usually used protic solvents such as methanol and ethanol.

37. Sodium Borohydride Reduction of Camphor (endo) (exo) In this case, approach by borohydride from the upper side is sterically hindered by the bridge methyl group. The result is a predominance of exo alcohol.

38. 38 Preparation of Grignard Reagents Grignard reagents react with aldehydes, ketones, and carboxylic acid derivatives Grignard reagents are made by adding the halogenoalkane to small bits of magnesium in a flask containing ethoxyethane (commonly called diethyl ether or just "ether"). The flask is fitted with a reflux condenser, and the mixture is warmed over a water bath for 20 - 30 minutes. A Grignard reagent has a formula RMgX where X is a halogen, and R is an alkyl or aryl (based on a benzene ring) group.

39. 39 Grignard reagents are used to prepare alcohols: Primary alcohol Secondary alcohol Tertiary alcohol

40. Nucleophilic Addition Reactions Of Aldehydes And Ketones  The C=O bond of aldehydes and ketones reacts with nucleophiles (such as H–, an organometallic reagent, or –CN) in nucleophilic addition reactions.  Nucleophiles add more rapidly to aldehydes than ketones because of steric and electronic effects.  Reaction of a phosphonium ylide (ylid) with an aldehyde or ketone forms an alkene in the Wittig reaction.

41.  The Wittig reaction is an important method for the formation of alkenes.  The double bond forms specifically at the location of the original aldehyde or ketone.  Ylides are neutral molecules but have +ve and -ve centers on adjacent atoms that are connected by a s bond.  The ylid is prepared via a two step process:

42. Wittig Reaction: The Wittig reaction is an important method for the formation of alkenes. The double bond forms specifically at the location of the original aldehyde or ketone. Ylides are neutral molecules but have +ve and -ve centers on adjacent atoms that are connected by a s bond. The ylide is prepared via a two step process: An SN2 reactioan between triphenyl phosphine and an alkyl halide followed by treatment with a strong base such as an organolithium reagent.

43. Step 1: The nucleophilic C of the ylid Wittig reagent adds to the electrophilic C in the polar carbonyl group, electrons from the C=O π bond are used to form a σ bond to the +ve P atom. This creates a cyclic intermeiate called an oxaphosphetane. Step 2: Decomposition of the intermediate by breaking the C-P and C-O σ bonds leads to the formation of the C=C π bond of the alkene and triphenyl phosphine oxide. Wittig Reaction:

44. 44  The Wittig reaction is completely regioselective.  This reaction is the best way to make a terminal alkene.  Stable ylides form primarily E isomers, and unstabilized ylides form primarily Z isomers.  Stable ylides have a group (C=O) that can share the carbanion’s negative charge.

45. Mapping of Ketone Reaction:

46.  Carbonyl Condensation  Micheal Reaction Aldol Claisen

47. Aldo Condensation of Aldehyde  Reagents : commonly a base such as NaOH or KOH is added to the aldehyde.  The reaction involves an enolate reacting with another molecule of the aldehyde.  Remember enolates are good nucleophiles and carbonyl C are electrophiles.  Since the pK a of an aldehyde is close to that of NaOH, both enolate and aldehyde are present.  The products of these reactions are β-hydroxyaldehydes or aldehyde-alcohols = aldols.  The simplest aldol reaction is the condensation of ethanal. Nucleophilic addition Aldehyde

48. Aldo Condensation of Ketones Nucleophilic addition  Reagents : commonly a base such as NaOH or KOH is added to the ketone.  Although ketone enolates are good nucleophiles, the aldol condensation of ketones is not particularly successful.  Because : Ketones are less reactive than aldehydes towards nucleophilic addition due to steric and electronic effects.  These aldol products can often undergo dehydration (loss of water) to give conjugated systems (an ellimination reaction) Ketone α,β-unsaturated aldehyde

49. Aldol Condensation  Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldehyde  The  -hydroxy aldehyde product is aldol (aldehyde + alcohol)  This is a general reaction of aldehydes and ketones

50. MECHANISM OF THE ALDOL CONDENSATION Step 1: First, an acid-base reaction. Hydroxide functions as a base and removes the acidic α-hydrogen giving the reactive enolate. Step 2: The nucleophilic enolate attacks the aldehyde at the electrophilic carbonyl C in a nucleophile addition type process giving an intermediate alkoxide. Step 3: An acid-base reaction. The alkoxide deprotonates a water molecule creating hydroxide and the β-hydroxyaldehydes or aldol product

51. MECHANISM OF THE DEHYDRATION OF THE ALDOL PRODUCT Step 1: First, an acid-base reaction. Hydroxide functions as a base and removes an acidic α-hydrogen giving the reactive enolate. Step 2: The electrons associated with the negative charge of the enolate are used to form the C=C and displace the leaving group, regenerating hydroxide giving the conjugated aldehyde.

52. Predicting Aldol Products The product will have an alcohol and a carbonyl in a 1,3 relationship (a beta-hydroxy carbonyl)

53. The Claisen Condensation Reaction type : Nucleophilic Acyl Substitution The Claisen condensation is the ester analogue of the Aldo condensation. Reagents : most commonly the base would be the alkoxide, R'O - The reaction involves an ester enolate reacting with another molecule of the ester. Remember enolates are good nucleophiles and the ester carbonyl C are electrophilic. Note that the product is the original ester with an acyl group added i.e. an acylation reaction has occurred. The products of these reactions are β-ketoesters which are important, useful synthetic intermidiates.. ester

54. MECHANISM OF THE CLAISEN CONDENSATION Step 1: First, an acid-base reaction. The alkoxide functions as a base and removes the acidic a- hydrogen giving the reactive ester enolate. Step 2: The nucleophilic ester enolate attacks the carbonyl C of another ester in a nucleophile substitution process giving the tetrahedral intermediate. Step 3: The intermediate collapses, reforming the C=O, resulting in loss of the leaving group, the alkoxide, leading to the b-ketoester product.

55. Learning Check: Predict the product of Claisen condensation of ethyl propanoate

56. Solution: Predict the product of Claisen condensation of ethyl propanoate

57. Mixed Claisen Condensations  Successful when one of the two esters acts as the electrophilic acceptor in reactions with other ester anions to give mixed  -keto esters Β-Keto ester

58. Addition of carbanion to α,β-unsaturated ketones: The Michael Reaction Reagents : commonly bases such as NaOH or KOH. The first step is the formation of the enolate. Enolates tend to react with α,β-unsaturated ketones via conjugate addition. A conjugate addition with a carbanion nucleophile is known as the Michael reaction or Michael addition.

59. MECHANISM OF THE MICHAEL ADDITION Step 1: First, an acid-base reaction. Hydroxide functions as a base and removes the acidic a-hydrogen giving the reactive enolate. Step 2: The nucleophilic enolate attacks the conjugated ketone at the electrophilic alkene C in a nucleophilic addition types with the electrons being pushed through to the electronegative O, giving an intermediate enolate. Step 3: An acid-base reaction. The enolate deprotonates a water molecule recreating hydroxide and the more favorable carbonyl group.

60. Learning Check:  Make the following using a Michael Reaction:

61. Solution:  Make the following using a Michael Reaction:

62. Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with itself? 1. The benzene ring makes the carbonyl group unreactive towards aldol reactions. 2. A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction. 3. The molecule does not possess any hydrogens α to the carbonyl group. 4. Electrophilic aromatic substitution competes favorably with the aldol reaction. 5. Nucleophilic acyl substitution competes favorably with the aldol reaction. Learning Check:

63. Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with itself? 1. The benzene ring makes the carbonyl group unreactive towards aldol reactions. 2. A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction. 3. The molecule does not possess any hydrogens α to the carbonyl group. 4. Electrophilic aromatic substitution competes favorably with the aldol reaction. 5. Nucleophilic acyl substitution competes favorably with the aldol reaction. Solution:

64. Predict the aldol reaction product of the following ketone. 1. 2.3. 4.5. Learning Check:

65. Predict the aldol reaction product of the following ketone. 1. 2.3. 4.5.Solution:

66. What type of reaction occurs in a Claisen condensation? 1. electrophilic aromatic substitution 2. nucleophilic addition 3. hydrolysis 4. nucleophilic acyl substitution 5. decarboxylation Learning Check:

67. What type of reaction occurs in a Claisen condensation? 1. electrophilic aromatic substitution 2. nucleophilic addition 3. hydrolysis 4. nucleophilic acyl substitution 5. decarboxylation Solution:

68. Select the correct Claisen condensation product for the following reaction. 1. 2. 3. 4. 5. Learning Check:

69. Predict the outcome of the following reaction. 1.2. 3. 4. 5.Solution: