Exam 4 Study Guide 1: Review of C-C bond forming reactions CHEM 212

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1 Exam 4 Study Guide 1: eview of - bond forming reactions EM 212 In an effort to summarize everything we have covered, this survey has been prepared. Use it to guide your studying for the next exam. 1. Direct alkylation of ketones, esters and nitriles: Used for the synthesis of α-alkyl substituted aldehydes, ketones, amides, esters and nitriles: Starting material: The aldehyde, ketone, amide, ester or nitrile you wish to alkylate G General eaction: G 1) LDA, TF, -78 o 2) -X: alkyl halide (1 o or 2 o ) G G = -, -, -Ar, -, -N 2 Bases used: lithium diisopropylamide (LDA) for quantitative removal of α-hydrogen Solvent: tetrahydrofuran (TF) onditions: -78 etro-synthesis: Look for the above fragment; for aldehydes, esters or amides that only have a-hydrogens on one side of the carbonyl or symmetrical ketones, this is an effective means of introducing alkyl groups. For asymmetric ketones, this is NT a good method, as mixtures of products will result. Use the following method: Direct alkylation of asymmetric ketones (cyclic or non-cyclic): Kinetic conditions will introduce the alkyl halide on the least hindered side (the one that was deprotonated fastest): 1) LDA, TF, -78 o 2) -X: alkyl halide (1 o or 2 o ) Thermodynamic conditions allow equilibration of the two possible enolates; the one with greater alkyl substitution on = forms in greater concentration (Zaitsev-like) 1) NaEt, Et, 25 o and up 2) -X: alkyl halide (1 o or 2 o )

2 2. Malonic Ester Synthesis: Used for the synthesis of a-alkyl substituted (mono- or di-) acetic acids: ' Starting Material: diethyl malonate, which is synthesized from a crossed laisen condensation (type 3): 1) NaEt, Et 2) 3) 3 General eaction (two or three steps): Step 1: Addition of alkyl group can be repeated for second alkyl group, place smaller one first 1) NaEt, Et, 25 o 2) =X: alkyl halide, 1 o or 2 o 3) 3 Bases used: β-dicarbonyls are very acidic for - acids, diethyl malonate has a pka of 10.7, ethoxide will quantitatively deprotonate as well as hydroxide Solvent: depends on base- ethanol for ethoxide, water for hydroxide Step 2: ydrolyze/decarboxylate treat with aqueous acid and heat this is the reverse Fischer Esterification and will convert the β-diester into a β-dicarboxylic acid, which loses 2 3, Δ Any aqueous acid, 3 Solvent: water onditions: heat] This can be a combined last step (e.g. as part of 3) in step 1) 2 Et 2 etro-synthesis: ' ealize that this acid can be readily inter-converted to acid halide, anhydride, ester or amide; 1 alcohols and aldehydes could also come from this fragment

3 3. Acetoacetic Ester Synthesis: Used for the synthesis of α-alkyl substituted (mono- or di-) acetones: ' Almost identical to malonic ester synthesis except 3 (or ) replaces one of the Et groups on diethyl malonate Starting Material: ethyl acetoacetate, which is synthesized from a laisen self-condensation: 1) NaEt, Et 2) 3 2 Et General eaction (two or three steps): Step 1: Addition of alkyl group can be repeated for second alkyl group, place smaller one first 1) NaEt, Et, 25 o 2) =X: alkyl halide, 1 o or 2 o 3) 3 Bases used: β-dicarbonyls are very acidic for - acids, ethyl acetoacetate has a pk A of 13, ethoxide will quantitatively deprotonate as well as hydroxide Solvent: depends on base- ethanol for ethoxide, water for hydroxide Step 2: ydrolyze/decarboxylate treat with aqueous acid and heat this is the reverse Fischer Esterification and will convert the β-ketoester into a β-keto-acid, which loses 2 3, Δ Any aqueous acid, 3 Solvent: water onditions: heat This can be a combined last step (e.g. 3) in step 1) 2 Et 2 etro-synthesis: ' 2 ealize that the acetoacetic ester synthesis (β-dicarbonyl is deprotonated, alkylated, and finally hydrolyzeddecarboxylated) can be applied to systems more complex than just 3 : 1) NaEt, Et 2) -X 3) 3, Δ

4 4. Aldol eaction/ondensation - Self Used for the synthesis of β-hydroxy aldehydes or ketones (aldol reaction) or α β-unsaturated aldehydes and ketones (aldol condensation): Starting Material: aldehyde or ketone with one or more α-hydrogens: General eaction: Divided into steps aldol reaction elimination/dehydration = aldol condensation Step 1: Self-condensation aldol reaction 2 () NaEt, Et emember, the enolate formed is the nucleophile in the nucleophilic addition reaction to another non-enolized carbonyl (here, identical to itself). Bases used: aldehydes and ketones are only deprotonated to a small extent in this equilibrium process, hydroxide or alkoxides are used; typical aldehyde or ketone pk A (for α-) ~20 β-dicarbonyls are very acidic for - acids, ethyl acetoacetate has a pk A of 13, ethoxide will quantitatively deprotonate as well as hydroxide Solvent: depends on base- ethanol for ethoxide, water for hydroxide Equilibrium is to right for aldehydes, to the left for ketones Not synthetically useful as shown Step 2: Elimination-dehydration heat slightly above the Step 1 reaction conditions and 2 is lost to form the unsaturation between α β carbons: () 2 () NaEt, Et () Δ, - 2 () onditions: heat Now synthetically useful etro-synthesis: for self condensation of ketones: = for self condensation of aldehydes: = α,β-unsaturated carbonyls can be made from aldol condensations (these are the precursors for the Michael and obinson ring annulation reactions). To do the retro-synthesis, remember to reverse the dehydration first, placing the hydroxyl on β-carbon. Make the cut between α and β-carbons, if the alcohol formed is 1, the other carbonyl was an aldehyde, if it is 2, it was a ketone.

5 5. Aldol eaction/ondensation rossed Used for the synthesis of β-hydroxy aldehydes or ketones (aldol reaction) or α β-unsaturated aldehydes and ketones (aldol condensation): Starting Material: aldehyde or ketone with one or more α-hydrogens: General eaction: There are three types of crossed aldol condensations that give only NE major product: 1) Where one of the two carbonyl compounds has no α-hydrogens; typically it is also a good electrophile (aldehyde) and used in excess donor (no 's) acceptor NaEt, Et (no 's) Δ, - 2 2) Where one of the two carbonyl compounds is far more acidic at α-carbon than the other (β-dicarbonyls vs. mono-carbonyls); in equilibrating conditions its enolate is in far greater concentration, and always acts as a donor. These always dehydrate! NaEt, Et donor acceptor 3) Directed Aldol form the enolate of one of the two carbonyls quantitatively with LDA (enolates cannot add to other enolates) in TF at -78, then add the second carbonyl 1) LDA, TF, -78 o 2) 3) 3 donor acceptor etro-synthesis: ' The difference with the crossed over the self-condensation is obviously that the donor and acceptor are not the same. The carbonyl still present in the product was the donor (through a-carbon) and the β-hydroxy component was the carbonyl that underwent nucleophilic addition (followed by dehydration to give the a-b unsaturated carbonyl. therwise perform retro-synthesis as for the self-condensation. You should be able to tell which of the three methods for crossed was used, however.

6 6. laisen ondensation Self Used for the synthesis of β-dicarbonyl compounds Starting Material: ester with one or more α-hydrogens: General eaction: Self-condensation laisen 2 1)NaEt, Et 2) 3 emember, the enolate formed is the nucleophile in the nucleophilic acyl substitution reaction to another nonenolized ester, the enolate adds, and the alkoxide leaving group is lost. Bases used: nucleophilic acyl substitution of can occur under the reaction conditions, so it needs to be made into a redundant reaction. Use the alkoxide that is the same as the alkoxy portion of the ester (90% of esters you will encounter are ethyl esters) Solvent: alcohol used to make alkoxide (usually ethanol) A protonation step is required, as under basic conditions, the product would be the stable enolate etro-synthesis: β-dicarbonyls can be made from laisen condensations (specifically, this is how ethyl acetoacetate is made for the acetoacetic ester synthesis). The α-carbon donor is the central carbon in this structure. To make the cut to see the acceptor, you will cleave a bond next to one of the carbonyls (this is different from aldol).

7 7. laisen ondensation rossed Used for the synthesis of β-dicarbonyl compounds Starting Material: For laisen, at least one component is an ester with a- s General eaction: There are three types of crossed laisen condensations that give only NE major product: 1) Where one of the two carbonyl compounds has no α-hydrogens is condensed with an ester; typically it is also used in excess (no α hydrogens) 1) NaEt, Et 2) 3 (no α hydrogens) 2) Where one of the two carbonyl compounds is far more acidic at α-carbon than the other (ketones vs. esters); in equilibrating conditions its enolate is in far greater concentration, and always acts as a donor. 1) NaEt, Et 2) 3 3) Directed laisen utilize diethyl carbonate or ethyl chloroformate as the acceptor; realize you can use ketones, aldehydes, amides or nitriles as the enolate donors 1) NaEt, Et 2) 3 Et Et Et Et l Et 1) NaEt, Et 2) 3 Et Et etro-synthesis: ' β-dicarbonyls from crossed laisen condensations can be worked backwards in a similar fashion. The α-carbon donor is the central carbon in this structure. To make the cut to see the acceptor, you will cleave a bond next to one of the carbonyls (this is different from aldol). ere you have to inspect both possibilities to see which half was the more appropriate donor, and like the crossed aldol, deduce which of the three crossed reactions could be used.

8 8. Intramolecular Aldol ondensation Intramolecular reactions occur at >10 3 the rate of intermolecular reactions; if a sufficiently long dicarbonyl compound is capable of self-condensing to form a 5 or 6 membered ring, it will occur over any intermolecular processes 1,4-dicarbonyls (aldehyde or ketone) undergo self-condensation to form 5-membered rings (cyclopentenones); 1,5- dicarbonyls form 6-membered rings (cyclohexenones) redraw NaEt, Et 1,4-dicarbonyl redraw NaEt, Et 1,5-dicarbonyl These always eliminate/dehydrate under the reaction conditions (which are identical to the intermolecular aldol) etrosynthesis follow the rules for the intermolecular aldol 9. Intramolecular laisen (Dieckmann) ondensation Similar to the intramolecular aldol, but a 5 or 6 membered cyclic β-dicarbonyl is formed. The diesters required are the 1,6 and 1,7 to form the five and six membered rings respectively. 1,6-diester redraw 1) NaEt, Et 2) 3 redraw 1) NaEt, Et 2) 3 1,7-diester emember in both cases, the products are β-dicarbonyls, which can readily be alkylated, then hydrolyzed and decarboxylated to give substituted cylcopentanones and cyclohexanones: 1) NaEt, Et 2) '-X 3) 3, Δ ' 1) NaEt, Et 2) '-X 3) 3, Δ '

9 10. Michael eaction Used for the synthesis of 1,5-dicarbonyl compounds Starting Material: An α,β-unsaturated carbonyl compound and a donor or General eaction: These work best if the Michael acceptor is relatively unhindered, and the donor is an easily formed enolate (βdicarbonyl) however, these will work to varying degrees of success with mono-carbonyl donors The Michael eaction emember, the enolate formed is the nucleophile in a 1,4 or conjugate nucleophilic addition reaction; remember that unlike 1,2-addition, the carbonyl is not lost in the reaction. 1) NaEt, Et 2) 3 1) NaEt, Et 2) 3 3, Δ Bases used: alkoxide or hydroxide Solvent: alcohol used to make alkoxide (usually ethanol) or water (hydroxide) If the β-dicarbonyl has a carboxylic acid derivative, it can be hydrolyzed and decarboxylated as shown etro-synthesis: decarboxylation before hydrolysis/ 1,5-dicarbonyls can most often be taken backwards through a Michael reaction. Do not forget the possibility that the donor was decarboxylated, as using this highly active enolate gives the best result. Also remember that aldol reactions are used to synthesize α,β-unsaturated carbonyls

10 11. obinson ing Annulation Note this is simply a Michael reaction followed by an intramolecular aldol condensation to give the six membered ring. Used for the synthesis of cyclohexenones: Starting Material: An α,β-unsaturated carbonyl compound (Michael acceptor) and a donor donor becomes acceptor for subsequent intramolecular aldol General eaction: As with the Michael reaction hese work best if the Michael acceptor is relatively unhindered, and the donor is an easily formed enolate (β-dicarbonyl) however, these will work with mono-carbonyl donors The obinson Annulation Step 1: Michael eaction: NaEt, Et Step 2: Intramolecular Aldol NaEt, Et Bases used: alkoxide or hydroxide Solvent: alcohol used to make alkoxide (usually ethanol) or water (hydroxide) etro-synthesis: ealize there are many ways to make cyclohexanones that we have covered; obinson Annulations are typically used for fused ring systems in particular. Also keep in mind that the Michael half and the aldol half of the reaction are in different domains and can easily be separated out and done step-wise. Likewise, you should do the same for the retro-synthesis. First undo the aldol condensation, then recognize the 1,5-dicarbonyl and undo the Michael. undo aldol undo Michael