Organic Chemistry, Third Edition. Chapter 24 Carbonyl condensations

rganic Chemistry, Third Edition Chapter 24 Carbonyl condensations 1

Review: enolates LDA, -78 C TF kinetic RX R = Me, 1 alkyl R Na TF, RT RX R = Me, 1 alkyl thermodynamic R enolates = nucleophiles React with electrophiles as in S N 2 reactions with alkyl halides 2

pka s pk a 19 pk a 17 R R 2 N pk a 24 pk a 33 Ph Ph P C 3 Ph pk a 22 N pk a 15 (in water) pk a 23 (in org) N pk a 15 (in org) R R R pk a 15 pk a 13 pk a 9 N pk a 24 (in org) N pk a 21 (in org) 3 + Cl 2 S 4 pk a 4.76 pk a 10 pk a 16 pk a 15.7 pk a -1.7 pk a -8 pk a -3 & 2 3

Review: enolates LDA, -78 C Br R' R' TF tbuk Br Et Bu Et React with alpha halo ketone, aldehydes and esters 1,4-dicarbonyls

Reaction of enolates with other electrophiles: cyclic ethers LDA, -78 C TF 1) 2) aq. acid LDA, -78 C TF 1) 2) aq. acid reaction with: epoxide (oxirane) = γ hydroxy-ketone oxacyclobutane (oxetane) = δ hydroxy-ketone

Condensation Reactions Between Two Carbonyl Compounds R' R R' R R" X R' R" X R X = Cl, R R' R R" X -X R' R R" 1,3-dicarbonyl X = alkyl or aryl or alkenyl (Adol) R' R" X R R' R" X R - R' R X R" X = alkyl or aryl or alkenyl 6

The Aldol Reaction In the aldol reaction, two molecules of an aldehyde or ketone react with each other in the presence of a base to form a β-hydroxy carbonyl compound. Base R R' -Base R' =, alkyl, aryl R' R R' R R' R R' R R' R R' R β-hydroxy ketone e.g. acetaldehyde NaEt Et 3-hydroxybutanal With R- as base, thermodynamic process 7

Adol Mechanism with aldehydes nucleophile formation of enolate Et nucleophilic addition pka 17 electrophile pka 16 Et Et Equilibrium reaction (reversible) Aldehyde equilibrium favors products 8

Adol Mechanism with ketones pka 19 NaEt nucleophile pka 16 + Et Et electrophile Equilibrium reaction (reversible) Ketone equilibrium favors starting materials Lower acidity of ketone (pka 19) compared with aldehyde (pka 17) 9

Retro-Aldol Reaction (ketones) Et 2 Et 10

Retro-Aldol Reaction (ketones) in Nature: Glycolysis of sugars (part of making ATP) C C 2 ATP ADP C C 2 P kinase C 2 C 2 ATP P ADP P C 2 C 2 P P C 2 aldolase P C 2 dihydroxyacetone phosphate 2 - C 2 P C 2 P + 4 ATP glceraldehyde phosphate 11

Adol Condensation Refers to an Adol reaction followed by dehydration (E 1CB ) to an α,β-unsaturated aldehyde or ketone. pka 17 NaEt Et pka 16 + Et Et E1cB eat - - α,β-unsaturated aldehyde enone ketones will undergo aldol condensations in high yield

Adol Condensation of ketons Adol reaction of ketone is not favorable. Adol condensation is favorable. pka 19 NaEt pka 16 + Et Et Et E1cB eat - - α,β-unsaturated aldehyde enone E1CB = Elimination Unimolecular conjugate base

Adol Condensation Even more favored by: aromatic groups or other extended conjugation NaEt Et ketones will undergo aldol condensations in high yield

Acid catalyzed Adol Condensation acid A A A A generally leads to elimination (not E1cB)

Acid catalyzed Adol Condensation A + A What is wrong with this mechanism??? ydroxide is a strong base. Can t have in presence of acid

Retrosynthetic Analysis of Aldol Products To utilize the aldol reaction in synthesis, you must be able to determine which aldehyde or ketone is needed to prepare a particular β-hydroxy carbonyl compound or α,β-unsaturated carbonyl compound that is, you must be able to work backwards in the retrosynthetic direction. 17

Retrosynthetic Analysis of Aldol Products 18

Identifying adol and adol condensation products adol reaction: beta hydroxy groups to aldehyde or ketone carbonyl adol condensation: enone

Crossed aldols Adol reaction A Na B A + B A + A B + A B + B Aldol condensations A Na eat B A + B A + A B + A B + B Problem: No selectivity, mixtures of products Solution: aldehyde without alpha protons

Crossed aldols Problem: No selectivity, mixtures of products Solution: aldehyde without alpha protons Na Better Solution: Directed adol. Make enolate qunatitatively in one step. Then add it slowly to excess of second carbonyl (electrophile). Na TF acid or base heat

Directed Aldol Reactions A directed aldol reaction is one that clearly defines which carbonyl compound becomes the nucleophilic enolate and which reacts at the electrophilic carbonyl carbon: [1] The enolate of one carbonyl component is prepared with LDA. [2] The second carbonyl compound (the electrophile) is added to this enolate. Both carbonyl components can have α hydrogens because only one enolate is prepared with LDA. When an unsymmetrical ketone is used, LDA selectively forms the less substituted kinetic enolate. 24

Crossed aldols Na heat TF 2) aqueous acid or 1) TsCl,pyridine 2) tbuk

Useful Transformations of Aldol Products The aldol reaction is synthetically useful because it forms new carbon carbon bonds, generating products with two functional groups. β-ydroxy carbonyl compounds formed in aldol reactions are readily transformed into a variety of other compounds. Figure 24.3 Conversion of a β-hydroxy carbonyl compound into other compounds 26

Use of Crossed Aldol Reactions [2] When one carbonyl component has especially acidic α hydrogens, these hydrogens are more readily removed than the other α atoms. As a result, the β-dicarbonyl compound always becomes the enolate component of the aldol reaction. 27

Active Methylene Compounds β-dicarbonyl compounds are sometimes called active methylene compounds because they are more reactive towards base than other carbonyl compounds. 1,3-Dinitriles and α-cyano carbonyl compounds are also active methylene compounds. 28

Example of Crossed Aldol Reactions In this type of crossed aldol reaction, the initial β-hydroxy compound always loses water to form the highly conjugated product. Figure 24.2 Crossed aldol reaction between benzaldehyde and diethyl malonate 29

Adol condensation reaction in biochemistry: tough meat Meat of older animals is tougher than that from young animals Toughening is due to cross-linking between collagen protein macromolecules N 2 N N N N N xidative deamination N N N N N Adol Condensartion N N N N N N N N N N N N N N N N N N N N N N

Directed Aldol Reactions Periplanone B is an extremely active compound produced in small amounts by the American cockroach. Its structure was determined using 200 µg isolated from more than 75,000 female cockroaches. Figure 24.4 A directed aldol reaction in the synthesis of periplanone B 1,2 addition to aldehyde 1,4 to vinyl ketone 31

Intramolecular Aldol Reactions Aldol reactions with dicarbonyl compounds can be used to make five- and six-membered rings. The enolate formed from one carbonyl group is the nucleophile, and the carbonyl carbon of the other is the electrophile. For example, treatment of 2,5-hexadienone with base forms a five-membered ring. 2,5-exanedione is called a 1,4-dicarbonyl compound to emphasize the relative positions of its carbonyl groups. 1,4-Dicarbonyl compounds are starting materials for synthesizing five-membered rings. 32

Use of Crossed Aldol Reactions When 2,5-hexanedione is treated with base in Step [1], two different enolates are possible enolates A and B, formed by removal of a and b, respectively. Although enolate A goes on to form the five-membered ring, intramolecular cyclization using enolate B would lead to a strained three-membered ring. Because the three-membered ring is much higher in energy than the enolate starting material, equilibrium greatly favors the starting materials and the three-membered ring does not form. 34

Intramolecular Aldol Reactions In a similar fashion, six-membered rings can be formed from the intramolecular aldol reaction of 1,5-dicarbonyl compounds. 35

The synthesis of the female sex hormone progesterone involves an intramolecular aldol reaction. Figure 24.5 Synthesis of Progesterone Using an Intramolecular Aldol Reactions 36

The Claisen Reactions In the Claisen reaction, two molecules of an ester react with each other in the presence of an alkoxide base to form a β-keto ester. Unlike the aldol reaction which is base-catalyzed, a full equivalent of base is needed to deprotonate the β-keto ester formed in Step [3] of the Claisen reaction. Since esters have a leaving group on the carbonyl carbon, loss of the leaving group occurs to form the product of substitution, not addition. 37

The characteristic reaction of esters is nucleophilic substitution. A Claisen reaction is a nucleophilic substitution in which an enolate is the nucleophile. Figure 24.6 Claisen Reaction Example of Nucleophilic Substitution 39

Claisen condensation reaction in biochemistry: Fatty acid synthesis SCoA SCoA + ACP + ACP CoA:ACP transacylase CoA:ACP transacylase SACP SACP NADP + + NADP+ SACP C 2 3-ketoacyl-ACP synthetase SACP!3-ketoacyl-ACP reductase SACP NADP + + NADP+ SACP 3-ydroxyacyl ACP dehydrase SACP!Enoyl-ACP reductase SACP Fatty acid NADP NADP N 2 S N N P P P N N N N N 2 - N P P - N N P - - N 2 N N - N P P - N N P - - N 2 N 2 N N

polyketide metabolites 42

Crossed Claisen Reaction Like the aldol reaction, it is sometimes possible to carry out a Claisen reaction with two different carbonyl components as starting materials. A Claisen reaction between two different carbonyl compounds is called a crossed Claisen reaction. A crossed Claisen is synthetically useful in two different instances: [1] Between two different esters when only one has α hydrogens, one product is usually formed. 44

Crossed Claisen: Side reaction Et bp 77 C Et Et bp 180 C ethyl acetoacetate Et Et Et bp 212 C bp 265 C ethyl 3-oxo-3-phenylpropanoate ow should reaction be set up? 45

Crossed Claisen Reaction [2] Between a ketone and an ester the enolate is always formed from the ketone component, and the reaction works best when the ester has no α hydrogens. The product of this crossed Claisen reaction is a β-dicarbonyl compound, not a β-keto ester. Vast excess of ethyl formate (low bp) 46

Forming β-dicarbonyl Compounds β-dicarbonyl compounds are also prepared by reacting an enolate with ethyl chloroformate or diethyl carbonate. Ethyl chloroformate reacts with ethoxide to form diethyl carbonate 47

Preparing β-keto Esters Reaction [2] is noteworthy because it provides easy access to β-keto esters, which are useful starting materials in the acetoacetic ester synthesis. In this reaction, Cl is eliminated rather than Et in Step [3] because Cl is a better leaving group, as shown in the following steps. 48

The Dieckmann Reaction An intramolecular Claisen reaction is called a Dieckmann reaction. Two types of diesters give good yields of cyclic products. 49

The Michael Reaction Et + 1) NaEt, Et 2) 3 +, heat 1,5 dicarbonyl R 2 C C 2 R R- R 2 C C 2 R R 2 C C 2 R pka 12 R EWG EWG R R- R 2 C C 2 R EWG R 2 C C 2 R EWG +, 2 Δ 2 C EWG Acid catalyzed decarboxylation removes one of C2R

The Michael Reaction The Michael reaction involves two carbonyl components the enolate of one carbonyl compound and an α,β-unsaturated carbonyl compound. Recall that α,β-unsaturated carbonyl compounds are resonance stabilized and have two electrophilic sites the carbonyl carbon and the β carbon. 52

Michael Acceptors The α,β-unsaturated carbonyl component is often called a Michael acceptor. 53

Michael Reaction Products When the product of a Michael reaction is also a β-keto ester, it can be hydrolyzed and decarboxylated by heating in aqueous acid. This forms a 1,5-dicarbonyl compound. 1,5-dicarbonyl compounds are starting materials for intramolecular aldol reactions. 55

Figure 24.7 Using a Michael reaction in the synthesis of the steroid estrone Using the Michael Reaction 56

Broader interpretation of Michael reaction: include enamines, amines and enolates as nucleophiles (Michael donors) Michael Acceptors EWG R NR' 2 N 2 CN EWG EWG EWG EWG EWG acrolein (often enolates add 1,2) Michael Donors R 2 C C 2 R R 2 C CR RC CR NC CN 2 N N 2 N 2 N RN 2 57

Recognizing Michael Adducts (Reaction Products) 2 N 2 N 2 N 58

Recognizing Michael Adducts (Reaction Products) Et Et Et 59

Michael additions in Nature Calicheamicin S S S N sugar Reduction S N sugar Michael Add Calicheamicins target DNA, causing strand scission. ne of the most potent anti-tumor agents known. S N sugar Drug for non-solid tumor cancer acute myeloid leukemia Bergman rearrangement S N sugar Diradical 60

The Robinson Annulation The Robinson annulation is a ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction. The starting materials for a Robinson annulation are an α,β-unsaturated carbonyl compound and an enolate. 61

The Robinson Annulation The Robinson annulation forms a six-membered ring and three new C C bonds two σ bonds and one π bond. The product contains an α,β-unsaturated ketone in a cyclohexane ring that is, a 2-cyclohexenone. To generate the enolate component of the Robinson annulation, in 2 or Et in Et are typically used. 62

Drawing Products of Robinson Annulation To draw the product of Robinson annulation without writing out the entire mechanism each time: [1] Place the α carbon of the carbonyl compound that becomes the enolate next to the β carbon of the α,β-unsaturated carbonyl compound. [2] Join the appropriate carbons together as shown. If you follow this method of drawing the starting materials, the double bond in the product always ends up in the same position of the sixmembered ring. 65

Synthesis Using the Robinson Annulation 67

Reactions Adol NaEt Et NaEt eat Intramolecular Adol NaEt Et Directed Aldol 1) Na, TF 2) Et Et 1) LDA, TF, -78 C 2) C 3 C 3) aq. work-up Et Et + Et C NaEt Et C 2 Et C 2 Et 1) LDA, TF, -78 C 2) Cl 68

Reactions Claisen NaEt Et Et Et Diekmann Et Et NaEt Et Et Michael Addition Et NaEt, Et Et 1,5 dicarbonyl Robinson Annulation Michael addition then intramolecular adol 69