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Chem 360 Jasperse Ch. 22 Notes + Answers. Chemistry 1

Chem 360-Jasperse Chapter 22 (Enolate Chemistry) Reaction Summary

PROTON as O OH , ROH 1. Ph Ph -Base-catalyzed keto- equilibrium -know mech (either direction) -know impact of on enol concentration

O O O base, ROH 2. Ph * Ph + Ph H H CH CH3 CH3 3 H optically active racemic - of α-chiral optically active carbonyls -Mech

HALOGEN as ELECTROPHILE O O excess Br (Cl ) 3. 2 2 Ph base Ph Br Br -Base catalyzed halogenation -with excess halogen, all α-hydrogens get replaced -Mech

O O excess I2 4. + CHI3 Ph excess NaOH Ph ONa -Iodoform reaction. -chemical test for methyl

O O Br (Cl ) 5. 2 2 Ph acid Ph Br H -Acid-catalyzed halogenation -can achieve selective mono-halogenation

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 2

ALKYL HALIDE as ELECTROPHILE O O 1. LDA 6. R Z 2. R-X Z -Enolate alkylation -strong LDA base required to completely deprotonate carbonyl -Mech -Ketones, , Amides, : doesn’t matter which kind of carbonyl -unsymmetrical ketones give problems -SN2 alkylation restricts R-X to active ones

O O O O 1. NaOR + O H3O , heat 7. R OR 2. R-X OR R -Enolate alkylation of 1,3-ketoester - base strong enough to completely generate enolate -Mech for alkylation -SN2 alkylation restricts R-X -position of alkylation is unambiguous -acid-catalyzed hydrolysis/

O O O O 1. NaOR + O H3O , heat 8. 2. R-X R RO OR RO OR HO R -Enolate alkylation of 1,3-diester -alkoxide base strong enough to completely generate enolate -Mech for alkylation -SN2 alkylation restricts R-X -acid catalyzed hydrolysis/decarboxylation -Final product is an ACID (Diester Acid)

O O O H H + O O O H3O , heat 9. -CO2 Z OH Z -CO2 Z O Z R R R R -decarboxylation of a 1,3-carbonyl acid -”Z” can be anything so that you end with a , , or acid at the end -know the mechanism for the decarboxylation, and acid-catalyzed enol to carbonyl isomerization -rate will be impacted by stability of the enol intermediate

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 3

ALDEHYDE/KETONE as ELECTROPHILE O OH O base 10. R R H ROH H R - -Mech

O Z OH O base, ROH Z O base heat 11. R R R Z H (or acid) Z R R - -Ketones as well as Aldehydes can be used -In ketone case, unfavorable aldol equilibrium is still drawn off to enone -In Aldehyde case, can stop at aldol if you don’t heat -Mech

Z OH O base, ROH Z O heat 12. R R H (or acid) Z R R -Aldol dehydration -Mech under basic conditions

O OH O O base, ROH O base heat 13. + R R' H R' Z Z (or acid) R' Z R R -Crossed Aldol (2 different carbonyls) -Many variations, but there must be some differentiation so that one acts selectively as the enolate and the other as the electrophile -Mech

O O O O base, ROH base heat 14. H (or acid) HO -Intramolecular aldol -Mech -many variations -Normally only good for 5, 6-membered rings

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 4

ESTER as ELECTROPHILE O O O base 15. R R OR ROH OR R -Claisen Reaction -Mech -Produces 1,3-ketoester

O O O O base 16. + R R' OR Z ROH R' Z ketone or R -Crossed Claisen -May include cyclic Claisen reactions -If the “enolate” carbonyl is a ketone, get a 1,3-diketone -If the “enolate” carbonyl is an ester, get a 1,3-ketoester -Mech

ENONE as ELECTROPHILE O O O O base 17. + R Z ROH Z enone ketone or ester R -Mech -”Michael Addition”

O O O O O base base 18. + R Z Z ROH ROH enone ketone or ester R heat Z R -”” -Mech -Michael addition gives 1,5-, then intramolecular aldol reaction-dehydration

WITTIG REACTION O X A X 19. + PPh3 A B Y B Y -Mech

Br PPh3+ 1. Ph3P 20. - R R1 2. BuLi (or some R R other base) 1 -Mech Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 5

Chem 360-Jasperse Chapter 22 (Enolate Chemistry) Reaction Mechanisms Summary • Note: in many of these reactions, I simply write in “base”. But for specific reactions, you need to recognize and specify the actual base that does the work. as ELECTROPHILE Ketone to Enol H-OR O base, ROH O OH 1. H Ph Ph Ph

O Ph

Enol Back to Ketone:

H O H-OR O O base, ROH 1.-reverse H Ph Ph Ph

O Ph

Deprotonation/Reprotonation to Racemize an optically active α-chiral center O O O base, ROH 2. * H-OR Ph Ph Ph H CH3 CH3 CH3 H optically active racemic or original. Protonation from the front gives enantiomer, from the back gives the original. The result is a 50/50 racemic mixture.

HALOGEN as ELECTROPHILE Base catalyzed halogenation. Sequential deprotonation/halogenation until all the α-hydrogens are replaced. • Note: addition of an electronegative, -withdrawing halogen stabilizes subsequent anion formation. As a result, the bromoketone formed after the first substitution is actually more acidic and therefore more reactive than the original ketone. For this reason you can’t just stop with a single halogenation under base conditions. (But you can under acid conditions, via an enol rather than enolate mechanism.)

O O O O Br-Br base Br-Br O base 3. Ph Ph Ph Ph Ph Br Br H H excess H Br Br2 H Br

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 6

ALKYL HALIDE as ELECTROPHILE With Strong LDA as Base, using a Monocarbonyl O N(iPr)2 O R-Br O 6. H R Z Z Z

1. Z can be anything: works for ketones, esters, aldehydes, esters,… 2. “LDA” is diisopropylamine, provides the nitrogen anion shown 3. strong LDA base required to completely deprotonate carbonyl. The base strength enables the enolate to form completely, no equilibrium or reversibility issues. 4. unsymmetrical ketones give isomer problems. If there are α-hydrogens on both left and right side of ketone, which will get deprotonated selectively? 5. SN2 alkylation restricts R-X to active ones (ideally primary or allylic/benzylic…) 6. Sequencing: the LDA must be added first, allowing the enolate to form completely; then the alkyl halide is added subsequently. If you add the halide at the beginning, it reacts with LDA 7. LDA deprotonates the carbonyl rather than adding to the carbonyl carbon for steric reasons

Using 1,3-, Such that Weaker Oxygen Bases are Strong Enough Strong LDA as Base, using a Monocarbonyl

O O O O O O R-Br OR 7. R OR R OR R OR H H H H R Test Responsible

+ H , H2O OH + O O O O H , H2O O heat heat R OR R OH R R several R enol R ketone R R steps keto-ester keto-acid ester hydrolysis decarboxylation acid catalyzed enol hydrolysis (ch. 18) Not Test Responsible

-alkoxide base strong enough to completely generate enolate -SN2 alkylation restricts R-X -acid-catalyzed hydrolysis/decarboxylation -not test responsible for the acid/catalyzed ester hydrolysis or the keto-acid decarboxylation mechanisms -you are responsible for the acid- enol hydrolysis (not detailed here, but was in Ch. 18)

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 7

O O O O O O R-Br OR 8. RO OR RO OR RO OR H H H H R Test Responsible

+ H , H2O OH + O O O O H , H2O O heat heat RO OR HO OH HO HO several R enol R R R steps acid ester-ester acid-acid ester hydrolysis decarboxylation acid catalyzed enol hydrolysis (ch. 18) Not Test Responsible

-alkoxide base strong enough to completely generate enolate -SN2 alkylation restricts R-X -acid-catalyzed hydrolysis/decarboxylation -not test responsible for the acid/catalyzed ester hydrolysis or the keto-acid decarboxylation mechanisms -you are responsible for the acid-catalysis enol hydrolysis (not detailed here, but was in Ch. 18)

H H + O O bond O O heat O H , H2O O rotation -CO2 9. Z OH Z O Z Z slow (ch. 18 R R enol R mech) ketone R step or acid decarboxylation Not Fully Test Responsible. But must know that ENOL is key intermediate that forms in the slow step. What is good for the enol (and it's ) accelerates the decarboxylation

-decarboxylation of a 1,3-carbonyl acid -”Z” can be anything so that you end with a ketone, aldehyde, or acid at the end -rate will be impacted by stability of the enol intermediate (more highly substituted enol alkene is better; conjugated enol alkene will form faster….) -since the mechanism depends on the conversion of the left carbonyl into an enol, are limited to 1,3-carbonyl acids. If you have a 1,2-carbonyl acid or a 1,4- carbonyl acid (etc), the formation of an enol will not be possible and the decarboxylation will not occur

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 8

ALDEHYDE/KETONE as ELECTROPHILE

Simple Aldol Reaction, giving a β-hydroxy-carbonyl. In which the same carbonyl functions as both enolate precursor and electrophile.

O O O O O OH O R H-OR 10. H OR R H H H R H H H R H R R R

-Deprotonate-react-protonate -Notice in this case that it’s the same carbonyl that functions as both the enolate precursor but also as the electrophile.

Aldol Condensation, giving an enone. In which the initial aldol product undergoes dehydration. O base Z OH O Z OH O Z O OR 11. R R R R Z Z Z Z R H Aldol R R formation (see #10) -The aldol product is formed as shown in mechanism 10. But under extended opportunity or heat, the product β- is eliminated to give the enone. -The elimination mechanism involves deprotonation to enolate, followed by extrusion -Ketones as well as Aldehydes can be used -In ketone case, unfavorable aldol equilibrium is still drawn off to enone -In Aldehyde case, can stop at aldol if you don’t heat and/or if you stop quickly enough

General Dehydration of β-hydroxy Carbonyls to Give α,β-unsaturated carbonyls Z OH O Z OH O Z O OR 12. R R R Z Z Z R H R R

-Aldol dehydration -Mech under basic conditions - β-hydroxy Carbonyls can also eliminate water to give enones under acid conditions, via a different mechanism. Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 9

Crossed Aldol Reaction, in Which One carbonyl compound serves selectively as the Enolate Precursor and a different one (usually aldehyde) as the electrophile

O O O O O OH O OR R' H-OR 13. H H R' Z Z R' Z Z H R H R R R Deprotonate Eliminate hydroxide (see mech 12)

H O R' Z R -Crossed Aldol (2 different carbonyls) -Many variations, but there must be some differentiation so that one acts selectively as the enolate and the other as the electrophile -because aldehydes are so much more reactive as , and because ketones are so much weaker as electrophiles and even when they do function as electrophiles the addition is reversible, crossed aldols between ketones and aldehydes work well, with the ketone reacting as the enolate and the aldehyde as the electrophile. -The mechanisms for the addition and also the subsequent possibly dehydration are essentially the same as for reactions 10-12.

Aldol Cyclization: Basically a crossed aldol reaction in which both carbonyls are tied together, and in which aldol reaction results in formation of a cyclic rather than an acylic β-hydroxy carbonyl

O O O O O base H OR, H-OR 14. heat H ROH H HO HO OR H-OR

O O O

H O -Intramolecular aldol -many variations -Normally only good for 5, 6-membered rings -There are often multiple α-hydrogens that can give multiple different . But since enolate formation is reversible, reaction proceeds via the enolate that can: react with the best electrophile. (Aldehyde rather than a ketone), and react to give the best ring size (5 or 6 membered rings >>> 7-membered rings >> 3-, 4-, or ≥8-membered rings)

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 10

ESTER as ELECTROPHILE Simple Claisen Reaction, giving a β-ketoester. In which the same ester functions as both enolate precursor and electrophile. O O O O O O O OR R 15. H OR R R OR OR OR OR R R R ORR

-Produces 1,3-ketoester -The alkoxide used as base should match the R-group found in the ester. For example, if the ester OR group is OMe, then the base should be NaOMe/MeOH. If the ester OR group is OEt, then NaOEt/EtOH should be used, etc. -Following enolate addition, the tetrahedral intermediate is *not* stable, and eliminates alkoxide to regenerate the carbonyl. -Note: Under basic reaction conditions, the keto-ester is normally deprotonated to a stabilized enolate. Following acidic workup, the enolate is reprotonated to give the actual keto-ester product. The enolate formation is actually crucial, because it “protects” the ketone from nucleophilic attack.

O O O O H+ workup O O OR R R R OR OR OR R H R R H

Crossed Claisen Reaction, giving either a β-ketoester or a 1,3-diketone. In which either a ketone or an ester functions as the enolated precursor, and a different ester functions as electrophile. O O O O O O O OR 16. H R' OR Z Z R' Z R' Z R R R ORR ketone or ester -Crossed Claisen -If the “enolate” carbonyl is a ketone, get a 1,3-diketone -When ketones and esters are mixed, the ketone usually functions as the enolate and the ester as the electrophile, because a) the ketone is more acidic, so makes enolate more easily, and b) addition/elimination to the ester is irreversible, whereas addition to ketone is reversible -If the “enolate” carbonyl is an ester, get a 1,3-ketoester. These work best if only one of the esters has α-hydrogens, so that you have just one enolate available. -May include cyclic Claisen reactions (see example below)

O O O O base O O

OR ROH OR H O O OR OR

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 11

ENONE as ELECTROPHILE “Michael Addition”: in which an enolate adds to the β-carbon on an enone to give a new enolate, and ultimated resulting in a 1,5-dicarbonyl compound.

O O O O O H OR O O 17. H OR Z Z Z Z enone R R R R ketone or enolate ester

-Enolate addition to the enone’s β−carbon results in formation of a new enolate, which is subsequently protonate. -When attack enones, there is often a competition between carbonyl addition (resulting in alkoxide formatin) versus β−addition (resulting in enolate formation). Which process happens depends on the .

O Z O Carbonyl Addition O O versus !+ + -Addition Z !+ ! " Z Z !+ Enolate Alkoxide Formation Formation

”Robinson Annulation”: in which Michael addition is followed by a cyclization reaction (either an aldol or a claisen reaction).

O O O O O H OR O O OR 18. H Z Z Z Z R enone R R H R ketone or enolate ester OR

O O O O O H OR H OR O Z HO HO If Z = R' Z R R' R' R R R If Z = OR O O

O R' R R -Steps 1-3 = Michael addition. -Steps 4-6 = Aldol reaction (or Claisen reaction, if using an ester) -Steps 7-8 = Dehydration reaction. -Enolate chemistry is central to each of these stages!

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 12

WITTIG REACTION O X A X 19. + PPh (and O PPh3 ) A B 3 Y B Y

O PPh3 O PPh3 A Y A Y B X B X

PPh PPh Br PPh3 PPh3 3 3 20. Base R R1 R R R R R R H 1 1 1

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 13

What is in Common for the Following Reactions, and How Do They Work? You should eventually be able to draw the mechanism for these (and other) reactions…

Key Intermediate

O O NaOH O 1 + Br-Br Ph Ph Ph

Br

O O NaOMe O O O O 2 + CH3-I OMe OMe OMe

CH3

O O O OH O NaOMe 3 + H

O O NaOH O O 4 + 2 H Ph Ph Ph

O O O O + NaOMe O 5 CH CH3 3 MeO Ph MeO MeO MeO Ph CH3

O O O NaOH O 6 + H O + Ph 2 Ph Ph Ph H CH H H C 3 CH3 3 H CH3 optically active racemic mixture

4 Things in Common KEY: Deprotonation of an α- hydrogen generates 1. Formation of a bond to the carbon α to a carbonyl ENOLATE anion, which is a good nucleophile

2. Basic/anionic reaction conditions

3. Involve an electrophile

4. At least one H α to a carbonyl is lost Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 14

TYPICAL MECHANISM: Via ENOLATE Anion

O O

Z ! Z ! Br CH CH -I 3 Br2 3 O O O O O OR (Base) Ph ! ! H H Z Ph Z Z O Z = H (Aldehyde) Z = R (Ketone) MeO Ph Z = OR (Ester) O O O O ! O ! Z Ph H2O Z Ph OMe Z O Enolate (original stereo ! Z forgotten) H O 2 H OH

! Z Under base conditions, a carbonyl compound with an α-hydrogen can be deprotonated to give a -stablized, delocalized “enolate” anion, which is nucleophilic at the α-carbon.

• Normal C-H bonds are very non-acidic. But C-H bonds α to a carbonyl are much more acidic because the resulting anion is resonance stabilized and is shared by the oxygen. O ! H H -20 -50 Ka = 10 Ka = 10

O

Stabilized Unstabilized

• The α-carbon has two other attachments in addition to the carbonyl and the H shown in this page. The other attachments will remain attached as spectators, and need to be accounted for in drawing products. • α-Hydrogens are only slightly less acidic than is water or hydrogens Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 15

• Acidity Table Acid Base Class Structure Ka Strength Anion Strength

Strong H-Cl 102 Max on Max on Acids Top Cl Bottom

Carboxylic O 10-5 O Acid R OH R O OH 10-10 O

1,3-Dicarbonyl O O 10-12 O O ! ! OMe OMe

H

-16 Water HOH 10 HO

-17 Alcohol ROH 10 RO Ketones and O 10-20 O Aldehydes ! H !

Ester O 10-24 O H a ! OMe OMe

Amine (N-H) (iPr) N-H 10-33 2 (iPr) N Li 2 “LDA”

-50 Alkane (C-H) RCH3 10 RCH2

H-A + B A + B-H Relative stability of anions dictates equilibrium

Notes to remember 1. Carbonyls acidify α-H’s (anion stabilized) 2. 1,3-Dicarbonyls are much more acidic than monocarbonyls (anion is more stabilized) 3. Ketones are more acidic than esters 4. A “lower” anion on the chart can favorably deprotonate any acid that’s “higher” on chart. Because any acid-base equilibrium will always favor the more stable anion. 5. “LDA” is strong enough to completely deprotonate ketones, esters, or 1,3-dicarbonyls 6. NaOH, NaOR can completely deprotonate a 1,3-dicarbonyl (but not ketones or esters) 7. NaOH, NaOR do not completely deprotonate ketones or esters, but do provide a usable equilibrium supply of the enolate that can procede to product in some reactions. Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 16

1. Rank the acidity of the hydrogens at the labeled positions, 1 being most acidic. Draw the three anions that would result from deprotionation at the three spots, and any pertinent resonance structures. O O c a b O b > a > c

O O O O c c Some resonance Site a: a b a b O O stabilization

O O c O O O O Site b: a b c c Excellent O a b a b resonance O O stabilization

O O Site c: c No resonance stabilization a b O 2. For the following compounds, record to what degree they would be deprotonated by

NaOCH3 or LDA [LiN(iPr)2] respectively. The basic choices are “totally” (>98%), “zero” (no enolate whatsoever) or “slightly” (definitely some equilibrium amount, but <10%). O O O O O Ph Ph Ph B C A D

LDA: totally totally none (no α-H) totally

NaOMe: slightly totally none (no α-H) slightly

3. For the following compounds, rank them according to which would have the greatest amount of enol isomer present at equilibrium, 1 being most enol, 4 being least.

O O O O O Ph Ph Ph B C A D B (enol OH stabilized by H-bonding; enol alkene stabilized by conjugation) > A (enol alkene stabilized by conjugation) > D (no enol stabilization, but at least some enol is possible) > C no enol whatsoever, because no α-hydrogens

4. Draw products for the following reactions O 2 Br2, 2NaOH O Ph H2O Ph Br Br O + 1 Cl2, H O Ph Ph H2O Cl O 1. 3 I , 3 NaOH, H O 2 2 O O O via and Ph I 2. H+ Ph OH Ph I Ph O I Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 17

5. Keto-Enol Mechanisms O OH H Ph Ph a. Draw the mechanism for conversion of the keto form to the enol form

b. Draw the mechanism for conversion of the enol form to the ketone

6. Draw the mechanism for the following O Br2, NaOH Ph H O 2

7. Try to draw the mechanism for the following.

O O O OH H NaOEt, EtOH Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 18

Draw products for the following alkylation reactions, often involving ester hydrolyses and thermal decarboxylations.

O 1. LDA O Ph Ph Ph 2. Me-I Ph 8.

O O 1. LDA

2. 9. Br

O O 1. NaOEt O O 2. EtO OEt Br EtO OEt 10.

1. NaOEt O O O O 2. Br EtO OEt EtO OEt 3. NaOEt 4. BrCH2CH=CH2 11.

1. NaOEt O O O 2. Br Ph HO

EtO OEt + 12. 3. H , H2O, heat Ph

1. NaOEt O O O 2. Br

OEt + 3. H , H2O, heat 13.

1. LDA O O

OEt OEt 2. Br 14.

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 19

15. Which of A, B, C, or D is the correct product for the following reaction? O O O O O O 1. NaOCH3 O O CH3 OH O O O O O O 2. CH3I CH A B C CH3 3 CH3 D B, via the best enolate

Some Synthetic Strategy Tips • Alkylation resulting eventually in an acid: from 1,3-diester, via NaOR, then subsequent ester hydrolysis/decarboxylation • Alkylation resulting eventually in a mono-ester: from ester using LDA • Alkylation resulting eventually in a mono-ketone, where unambiguous deprotonation was possible: from ketone using LDA • Alkylation resulting in a mono-ketone, where unambiguous LDA deprotonation would not have been possible: from keto-ester using NaOR, then subsequent ester hydrolysis/decarboxylation

Provide reagents for the following:

O O 1. NaOEt O EtO OEt 2. PhCH2Br HO Ph + 16. 3 . H , H2O, heat

O 1. LDA O EtO 2. BrCH2CH=CH2 EtO 17.

18. Which of the following would undergo decarboxylation? And which would go fastest? O O O O O O

OH OH OH OH A B O C O D Ph

D > A (the 1,3-carbonyl acids that can proceed to enol) B and C won’t, not 1,3 D > A because enol produced in rate-determining-step is stabilized by conjugation with the phenyl

19. Draw the mechanism for the following reaction. O O 1. LDA CH3

2. CH I 3 Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 20

Aldol Examples: Aldehydes/Ketones as Electrophiles

O OH O NaOH, H2O NaOH, H2O O

H H warmup 1. cold H

OH O O NaOH, H2O NaOH, H2O O Ph Ph Ph H cold H warmup H 2. Ph Ph

• With aldehydes, you can usually stop at the β-hydroxy carbonyl stage or proceed on to the α,β-unsaturated carbonyl, depending on time and temperature.

O O O NaOEt, EtOH HO NaOEt, EtOH

3. Heat

• With ketones as electrophiles, the aldol reaction to give the β-hydroxy carbonyl is normally reversible with an unfavorable equilibrium. However, while it is not possible to isolate high yields of the β-hydroxy ketone, further dehydration to give the enone is irreversible and can give good yields of the enone.

O O NaOMe OH O NaOMe O + H Ph MeOH MeOH 0ºC Ph warmup Ph 4. more time

• With two different carbonyl compounds, one must function selectively as the enolate precursor, and the other as the electrophile. • Since aldehydes are much more electrophilic, when mixed with a ketone the aldehyde will always be the electrophile • If there are more than one site where an enolate might form, the most acidic site that would give a stabilized anion will form preferentially

O O NaOEt OH O NaOEt O + Ph H OEt EtOH Ph OEt EtOH Ph OEt 0ºC warmup 5. more time

Comments • Basic • One carbonyl functions as the enolate nucleophile, a second carbonyl as the neutral electrophile. The enolate precursor and the electrophile carbonyl may be the same (examples 1-3) or different (examples 4 and 5) • Loss of an α-H, replaced by an α,β C-C bond. Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 21

All of the following can be made by an aldol-type reaction or an aldol-type

condensation (aldol followed by loss of H2O). Draw the carbonyl compound or compounds from which each is derived.

OH O O O example: + Ph O Ph O

Strategy: • Identify the carbonyl in the product, and mark off which are the α and β carbons. The key bond connection will have been between the α and β carbons. • β was originally a carbonyl (the electrophile carbonyl) • α originally had H’s (it was the enolate ) • Note: any attachments on the α and β carbons are spectators. If they are there at the end, they must have been attached at the beinning!

O OH O O

20.

OH O O (both enolate precursor and electrophile) H 21. H

O O O

H 22.

OH O O O Ph O Ph O 23.

24. Draw the mechanism for the following reaction.

O O NaOMe O OH + Ph MeOH Ph 0ºC Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 22

Provide products for the following aldol reactions.

O NaOH, H2O OH O NaOH, H2O H O Ph H Ph H cold H heat Ph H Ph 25. Ph

O O NaOMe, MeOH

heat 26.

OH O H O O NaOEt NaOEt O + EtOH Ph Ph Ph H H EtOH 0ºC heat 27.

O O NaOEt OH O NaOEt H O + Ph H EtOH EtOH 0ºC H Ph heat Ph 28. best enolate

O O O NaOH NaOH H H2O H2O O cold hot enolate HO leading to 29. 5-ring

O O O NaOCH3 NaOCH3 O H HOCH3 HOCH3 cold OH hot enolate leading to 30. 6-ring

31. Draw the mechanism for phase one and then phase two of the reaction in problem 28. Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 23

Provide products for the following Claisen reactions.

O NaOCH3 O O Ph OMe Ph OMe HOCH3 32. Ph

O NaOEt O O

OEt HOEt OEt 33.

O 1. NaOMe, MeOH O O 2. O O

OMe 2. NaOMe OMe 3. OMe 3. BrCH2CH=CH2 34.

1. NaOMe, MeOH O O O O 4. H OMe 2. NaOMe OMe 3. BrCH2CH=CH2 + 35. 4. H , H2O, heat

O O O O O 1. NaOCH3, HOCH3 2. OMe MeO OMe + 2. H , H2O, heat 36.

O O NaOMe O O + Ph OMe OMe MeOH Ph OMe 37.

O O O O NaOMe + OMe MeOH 38. Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 24

Draw the product, reagent, or starting material for the following Wittig reactions.

+ Combo 1: O Ph3P

Combo 2: + O 39. PPh3

1. Ph3P 2. BuLi Br Ph 40. 3.

O OH O 1. H2CrO4 2.

41.

1. PBr3 2. PPh3 OH Br PPh PPh3 3 3. BuLi 4.

42. Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 25

General Routes to Make • Wittig Reactions. o Very general o Useful for making more elaborate organics, because two subcomponents can be coupled to make a larger product. o Technically longer and more difficult than an aldol condensation, so should not be used to make enones when an aldol condensation could be used instead. • Aldol Condensations. o Great for making enones (α,β-unsaturated carbonyls). But limited to making enones. o If you see an enone target, make via aldol condensation. o Useful for making more elaborate organics, because two subcomponents can be coupled to make a larger product. • Elimination reactions (from either halides or ). o Not useful for building up carbon chain lengths. Simply involves transforming one functional group into another.

43. For the following alkenes, which method should you use, and what would be the immediate precursors that would be suitable?

Aldol O O + Ph Ph O

Wittig + Ph P O 3 or + O PPh3

44. Synthesis design. Design syntheses of the following products, starting from alcohols of 4 carbons or less. Some key reminder reactions: • PCC for oxidizing 1º alcohols to aldehydes

• H2CrO4 for oxidizing 2º alcohols to ketones • PBr3 for converting 1º or 2º alcohols to bromides needed for making Wittig reagents

O NaOMe O PCC OH + H O H H MeOH H heat (same thing)

+ Ph3P or + O O PPh3 PCC 1. PBr3 1. PBr3 2. PPh3 H CrO OH 2. PPh3 2 4 3. BuLi 3. BuLi HO HO OH

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 26

General: Enones as Electrophiles. Nucleophiles that attack enones must chooe between: • Carbonyl addition • β-Addition

O Z O Carbonyl Addition O O versus !+ + -Addition Z !+ ! " Z Z !+ Enolate Alkoxide Formation Formation

Carbonyl addition normally dominates with: • RMgBr • RLi

• NaBH4 • LiAlH4 • LiCCR

β- addition normally dominates with: • enolates of dicarbonyls • sometimes enolates of monocarbonyls (but not always)

• Cuprates (R2CuLi) 1. 4 Li Prep: 2RBr R2CuLi 2. 1 CuI

Draw the Products for the following Michael reactions O O O NaOEt O O + OEt EtOH OEt O 45.

O O O NaOEt O O + EtO OEt EtOH EtO OEt H3C O 46.

NaOEt OH O O EtOH O O O O + heat, long time -draw in the initial product, 47. second product, and third product

Chem 360 Jasperse Ch. 22 Notes + Answers. Enolate Chemistry 27

48. Draw the mechanism for the following reaction. (Claisen reaction).

O NaOCH3 O O OMe HOCH3 OMe

49. Draw the mechanism for the following reaction ().

O O O NaOEt O O + EtO OEt EtOH EtO OEt O

50. Draw the mechanism for the following reaction. (Robinson cyclization, involving sequential Michael reaction, aldol reaction, β−hydroxyketone dehydration.)

NaOEt O OH O O EtOH O O + via heat, and long time C B A O