1. Ch 16 Aldehydes and Ketones I

2. Introduction All aldehydes have a carbonyl group bonded on one side to a carbon and on the other to a hydrogen Examples: Ketone have carbons bonded to both sides of the carbonyl Examples:

3. Introduction The chemistry of the carbonyl group is central to the chemistry of most of the chapters to follow In this chapter, we will focus on naming aldehydes/ketones, preparing them, their physical properties, and on nucleophilic addition reactions that take place at their carbonyl groups

4. Introduction In the next chapter, we will study the chemistry of aldehydes and ketones that results from the acidity of the hydrogen atoms on the carbon atom adjacent to their carbonyl group

5. Nomenclature Aldehydes- – Drop the –e of the alkane name – Add –al – Since aldehydes are always at the end of the chain, no need to number – When other substituents are present, the carbonyl carbon is assigned position 1 – Examples:

6. Nomenclature Aldehydes attached to a ring system are named by adding –carbaldehyde to the end of the regular name Example

7. Nomenclature IUPAC names for Ketones- – Drop the –e of the alkane name – Add –one – The chain in numbered to give the carbonyl carbon the lowest possible number Common names for Ketones – Name the two groups attached to carbonyl followed by the word ketone – examples

8. Nomenclature Some ketones have common names that are retained in IUPAC: Examples: When it is necessary to name the aldehyde group as a prefix, it is the methanoyl group Ketones are named as prefixes as the alkanoyl group. Examples:

9. Physical Properties The carbonyl group is polar, therefore aldehydes and ketones are polar and have higher BP’s than hydrocarbons of similar MW Since ald/ket can not hydrogen bond to each other they have lower BP’s than corresponding alcohols

10. Physical Properties The carbonyl oxygen can form hydrogen bonds with water, so low MW ald/ket show appreciable water solubility

11. Synthesis of Aldehydes 1) Aldehydes by oxidation of primary alcohols – Covered in reactions of alcohols – Uses PCC – examples 2) Aldehydes by reduction of Acyl chlorides, esters, and nitriles – Carboxylic acids are reduced all the way to the alcohol because any aldehyde produced is immediately reduced.

12. Synthesis of Aldehydes – By using a derivative of the carboxylic acid, we can use a less powerful reducing agent, thus stopping at the aldehyde – There are 2 derivatives of LAH that are less reactive: – Lithium tri-tert-butoxyaluminum hydride – Diisobutylaluminum hydride (DIBAL-H) – Examples:

13. Synthesis of Aldehydes i)Aldehydes from acid chlorides: Recall that we learned how to make acid chlorides in the last chapter We can then use lithium tri-tert-butoxy aluminum hydride to reduce the acid chloride to the aldehyde: Mech:

14. Synthesis of Aldehydes ii) Aldehydes from Esters and nitriles- Both esters and nitriles can be reduced to aldehydes by the use of DIBAL-H Carefully controlled amounts of DIBAL-H must be used to avoid over-reduction The ester reduction must additionally be done at low temperatures

15. Synthesis of Aldehydes Mechanism for reduction of esters Mechanism for reduction of Nitriles Note: the oxygen in the aldehyde comes from added water! examples

16. Synthesis of Ketones Previously covered 3 ways: – 1) Ketones (and aldehydes) by ozonolysis of Alkenes – 2) Ketones from arenes by Freidel Crafts Acylations – 3) Ketones from secondary alcohol oxidation

17. Synthesis of Ketones Ketones from Alkynes- – Alkynes can undergo hydration similar to double bonds – The reaction is usually done with HgSO4 and aqueous sulfuric acid – However, after the first addition of water, a very unstable vinylic alcohol is formed.

18. Synthesis of Ketones – This vinylic alcohol can rearrange to form a ketone – The rearrangement is acid catalyzed and involves the loss of a proton from the hydroxyl group, the addition of a hydrogen to the other carbon of the double bond and the relocation of the double bond. – Mechanism:

19. Synthesis of Ketones – This kind of rearrangement is called a tautomerization. – Vinylic alcohols are often called enols. – Since the product of the rearrangement is a ketone, these types of rearrangements are often called keto-enol tautomerizations – Example:

20. Synthesis of Ketones – The addition of water to alkynes follows Markovnikov’s rule, so when using terminal triple bonds, you will always get the ketone, only exception is ethyne. – With internal alkynes, you usually get mixed results. – Examples:

21. Synthesis of Ketones Ketones from Lithium Dialkylcuprates – This is a variation of the Corey-Posner-Whiteside- House alkane synthesis done at very low temperature – The dialkyl cuprates are mixed with an acid chloride in ether to yield the ketone – example

22. Synthesis of Ketones Ketones from Nitriles – Treating a nitrile with either a grignard reagent or an organolithium reagent followed by hydrolysis yields a ketone – Examples: – Note: Reminder, nitriles can be made by adding NaCN to an alkyl halide via Sn2 reaction

23. Synthesis of Ketones See solved problem 16.5 and practice problem 16.4 on page 731

24. Nucleophilic Addition to the Carbon- Oxygen Double Bond The most characteristic reaction of aldehydes and ketones is nucleophilic addition to the carbon-oxygen double bond Examples: Because the carbonyl is trigonal planar, the nucleophilic attack may occur from the top or the bottom, so therefore if a stereogenic is formed, it is racemic

25. Nucleophilic Addition to the Carbon- Oxygen Double Bond The partial positive charge on the carbonyl carbon makes it suseptible to nucleophilic attack The first mechanism takes place with strong nucleophiles

26. Nucleophilic Addition to the Carbon- Oxygen Double Bond The second mechanism shows that the reaction can also be acid-catalyzed This mechanism occurs when the carbonyl is treated with strong acid in presence of weak nucleophile

27. Nucleophilic Addition to the Carbon- Oxygen Double Bond Many nucleophilic additions to the carbonyl are reversible The results of the reaction depend on the equilibrium Relative Reactivity – In general, aldehydes are more reactive than ketones – This is due to both steric and electronic factors

28. Nucleophilic Addition to the Carbon- Oxygen Double Bond Addition of Alcohols- – Hemi-acetals- a compound that contains a carbon bonded to both an –OR group and –OH group – General Reaction – Most open-chain hemiacetals are not sufficiently stable to allow their isolation – Cyclic hemiacetals with 5 or 6 membered rings are much more stable

29. Nucleophilic Addition to the Carbon- Oxygen Double Bond – Most simple sugars exist primarily in a cyclic hemiacetal form – Example – Ketones can form hemiacetals as well – We can show both an acid catalyzed and base catalyzed mechanism – Examples:

30. Nucleophilic Addition to the Carbon- Oxygen Double Bond – Once a hemiacetals form, the addition of another alcohol is possible to form an acetals – Acetal- has two –OR groups bonded to the same carbon atom: – Like hemiacetals, open chain acetals are not favored but cyclic acetals are. – Acetals as protecting groups:

31. Nucleophilic Addition to the Carbon- Oxygen Double Bond Addition of primary and secondary amines – Primary amines react with ald/ket to form imines – An imine has a C-N double bond – Secondary amines react with ald/ket to form enamines – An enamine has an amino group bonded to carbon- carbon double bond. – Examples – Mechanisms:

32. Nucleophilic Addition to the Carbon- Oxygen Double Bond – The pH for these reactions must be monitored – If it is too low, the primary amine will protonate – If It is too high, insufficient protons are available for the reaction – pH range of 4-5 optimal Make sure to review the Oxime, Hydrazones, and Semicarbozone sections in the book.

33. Nucleophilic Addition to the Carbon- Oxygen Double Bond Enamines example and mechanism: See table 16.2, page 745-746, reactions of aldehydes and ketones with derivatives of ammonia

34. The addition of Hydrogen Cyanide The addition of HCN to a carbonyl results in compounds called cyanohydrins Highly hindered ketones do not react example. Mechanism This reaction is very useful in organic synthesis because the cyano group can be converted to other functionalities, plus it adds one carbon to the chain example

35. The addition of Ylides: The Wittig Reaction Aldehydes and Ketones react with phosphorus ylides to give alkenes Ylides- a neutral molecule having a negative charged carbon adjacent to a positive charged heteroatom. Ex.

36. The addition of Ylides: The Wittig Reaction Although a mixture of E and Z isomers results, the Wittig Reaction is better than most other alkene synthesis reactions because there is no ambiguity as to the location of the double bond. The phosphorus ylides are prepared from triphenylphosphine and a primary or secondary alkyl halide Ex Mechanism

37. The addition of Ylides: The Wittig Reaction The first step is a simple Sn2 reaction with the phosphorous displacing the halide The second step is an acid-base reaction in which a strong base, usually an alkyllithium or phenyl lithium, removes a proton from the carbon attached to the phosphorous

38. The addition of Ylides: The Wittig Reaction Wittig Reaction mechanism Example

39. The addition of Ylides: The Wittig Reaction A widely used variation of the Wittig reaction is the Horner-Wadsworth-Emmons modification Instead of using triphenyl phosphine to form the triphenyl phosphonium salt, a phosphonate ester is used The advantage to this modification is that the major product is usually the (E)-alkene isomer

40. The addition of Ylides: The Wittig Reaction The typical bases used are Sodium Hydride, NaH, potassium t-butoxide, and butyl lithium Examples:

41. The addition of Organometallic reagents: The Reformatsky Reaction Earlier, we saw that Grignard, organolithium, and sodium alkynides could add to aldehydes and ketones to give a wide variety of alcohols Examples: Now, we examine a similar reaction that involves the addition of an organozinc reagent This reaction extends the carbon skeleton of an aldehyde and ketones and yields a β-hydroxy ester

42. The addition of Organometallic reagents: The Reformatsky Reaction The reaction involves treating an aldehyde or ketone with an α-bromo ester in the presence of zinc metal, typically in Benzene Reaction: Mechanism:

43. The addition of Organometallic reagents: The Reformatsky Reaction Because the organozinc is less reactive than a grignard reagent, it does not add to the ester group The β-hydroxy ester product can easily be dehydrated to an α,β-unsaturated ester examples

44. Oxidation of Aldehydes and Ketones Aldehydes are much easier to oxidize than ketones. Examples:

45. Baeyer-Villiger Oxidation of Aldehydes and Ketones This reaction converts aldehydes and ketones to esters, using a peroxycarboxylic acid (RCO 3 H) such as m-chloroperoxybenzoic acid (mCPBA) Example Mechanism

46. Baeyer-Villiger Oxidation of Aldehydes and Ketones Notice that we showed the phenyl group migrating over to the oxygen The tendency of a group to migrate is called it migratory aptitude Studies of the Baeyer-Villiger oxidation and other reactions have shown that the migratory aptitude of groups is:

47. Make sure to check out the synthetic connections at the end of the chapter.