Enols and Enolates - Organic Chemistry - Lecture Notes, Study notes of Organic Chemistry

Download Enols and Enolates - Organic Chemistry - Lecture Notes and more Study notes Organic Chemistry in PDF only on Docsity! 1   Enols and Enolates There are two major types of reactions of carbonyl compounds. (1) Attack of nucleophiles on the carbonyl carbon. R C O R'Nu:- + R C R' Nu O- (2) Reaction at the alpha-carbon based on removal of the alpha-proton. Removal of the α- proton produces an anion at the α−carbon. The α−carbon is now a nucleophile as we shall see. R3 C H R2 C O R1 B:- R3 C R2 C O R1 R3 C R2 C R1 O- enolate H solvent R3 C R2 C R1 O H enol Acidity of the Alpha-Proton Designate carbons next to the carbonyl with Greek letters. C C H C O C αβγ The proton at the α-carbon is exceptionally acidic due to: (1) The inductive effect of the carbonyl. The carbonyl group is a strong electron- withdrawing group and helps to remove electron density from the α-carbon. C C O H docsity.com 2 (2) Resonance stabilization of the resulting anion. The negative charge from deprotonation of the α−carbon is partially delocalized onto the carbonyl oxygen. C C O H B:- C C O C C O- The pKa’s are in the 16-20 range. Aldehydes have lower pKa’s than ketones because in ketones the extra alkyl group donates electrons to make the carbonyl carbon less electron deficient and less of an electron-withdrawing group. C C O CH3 H H H acetone pKa 19.3 C C O H H H acetophenone pKa 18.3 C C O H H H H acetaldehyde pKa 16.7 Electron withdrawing substituents will increase the acidity. C C O CH3 H H Cl pKa 14.1 Benzene rings attached to the α-carbon also increase the acidity of the α-proton by helping to stabilize the resulting anion through resonance delocalization. CH3 C O CH H pKa 15.9B:- CH3 C O H C CH3 C O C H CH3 C O C HCH3 C O C H Esters can also form enolates but the α−proton of esters is much less acidic because the oxygen of the ester is an electron-donating group. The oxygen is more electronegative docsity.com 5 C C O CH3 H CH3CH2 H N CH CH CH3 CH3CH3 CH3 + slow fast C C CH3CH3CH2 H O- + N CH CH CH3 CH3CH3 CH3 H pKa ~16 pKa 36 Keq 1020 ~100% Esters are also quantitatively converted to the enolate. C C O OCH3 H CH3CH2 H N CH CH CH3 CH3CH3 CH3 + slow fast C C OCH3CH3CH2 H O- + N CH CH CH3 CH3CH3 CH3 H pKa ~25 pKa 36 Keq 1011 ~100% As we will see, LDA is a very useful reagent for alkylation and acylation of aldehydes, ketones and esters. Enolate Regiochemistry With aldehydes and esters there is only one α−carbon but ketones have two and deprotonation can occur at either of them. When the ketone is not symmetrical both positions must be considered. Two possible enolates are possible. If there is a difference in steric hindrance between the two possible enolates, it is possible to control which enolate forms by controlling the reaction conditions. In general the less hindered α-proton can be removed by using a strong non-hindered base such as LDA at low temperatures, typically -78°C, the temperature of dry ice (solid carbon dioxide) and an acetone bath. The less hindered proton will be removed faster and using a very strong base such as LDA ensures that the reaction is irreversible. This is called kinetic control. And the more substituted proton can be preferentially removed under conditions, which allow for equilibration since removal of the more substituted α-proton leads to the formation of the more substituted enolate. This is the more stable enolate and this is called thermodynamic control. A weaker base such as an alkoxides or hydroxide is used in conditions in which the reaction is readily reversible. docsity.com 6 O H CH3 H H LDA, -78°C THF O H CH3 kinetic enolate, less hindered, removed faster at low temperature NaOH or NaOCH2CH O H H CH3 thermodynamic enolate, more stable, formed under equilibrating conditions Aldol Condensation When aldehydes and ketones with α-hydrogens in the pKa range 16-20 are treated with a base such as hydroxide or alkoxide, significant amounts of enolates are produced. The enolate can react with the starting aldehyde or ketone to give the aldol product. CH2 C O HR NaOH H2tO CH C O HR C OH H CH2R aldol product This is called a condensation because two molecules of the starting material combine to give one molecule of product. This is called the aldol product because it contains an aldehyde (ald-) and an alcohol (-ol). For example: CH2 C O HCH2CH32 NaOH H2tO CH C O HCH2 C OH H CH2CH2 CH3 CH3 The mechanism is as shown below. At equilibrium, both the enolate and starting aldehyde are present. The enolate is a nucleophile and will attack the carbonyl carbon of another molecule of starting material. docsity.com 7 CH C O HCH2CH3 H HO- CH C O HCH2CH3 CH2 C O HCH2CH3 CH C O HCH2CH3 C H O_ CH3CH2CH2 H O H CH C O HCH2CH3 C H OH CH3CH2CH2 If the initial aldol product is heated in the basic reaction conditions, the molecule will dehydrate to give an α,β−unsaturated carbonyl. CH C O HCH2CH3 C H OH CH3CH2CH2 heat NaOH C C O HCH2CH3 C HCH3CH2CH2 + H2O α β Note here that the new double bond is conjugated with the carbonyl group, making this a particularly stable double bond. Usually dehydration does not occur in basic conditions but it does here for two reasons: (1) The α−proton next to the carbonyl is quite acidic. (2) The new double bond is conjugated with the carbonyl. The reaction occurs in two steps. First the enolate forms and then loss of hydroxide, HO-, occurs to give the α,β−unsaturated carbonyl. C C O HCH2CH3 C H OH CH3CH2CH2 H HO- C C O HCH2CH3 C H OH CH3CH2CH2 enolate C C O HCH2CH3 C HCH3CH2CH2 + -OH The aldol reaction is reversible and the equilibrium for aldol reactions with ketones are much less favorable than they are for aldehydes. The equilibrium generally favors the starting ketone rather than the aldol product. Recall that ketones are less reactive than aldehydes. (1) They form a lower concentration of enolate and (2) the carbonyl carbon of the ketone is less electrophilic than it is for aldehydes. This is due both to steric hindrance and to the electron-donating ability of the extra alkyl group of the ketone. docsity.com 10 H C O CH CH2 CH3 H + H C O CH CH3 H Na + -OH Na+ -OH H C O- CH CH2 CH3 H C O CH2 CH2 CH3 H2O H C CH2 CH2 CH3 OH CHC O H CH2CH3H C O CH2 CH3 H2O H C O CH CH2 CH3 CH OH CH2CH3 H C CH CH3 O- H C O CH2 CH3 H C O CH CH3 CH CH2CH3 OH H C O CH2CH2CH3 H C O CH CH3 CH CH2CH2CH3 OH2-ethyl-3-hydroxy-hexanal 2-methyl-3-hydroxy-hexanal 2-methyl-3- hydroxypentanal 2-ethyl-3-hydroxypentanal The reaction is synthetically useful and gives one major product if (1) one of the substrates cannot form an enolate or (2) one of the reactants is much more electrophilic (i.e. more reactive to nucleophiles) than the other reagent. Formaldehyde is an example of a reagent that is highly reactive to nucleophiles like enolates. The following are examples of aldehydes and ketones that do not have α-protons and cannot enolize: H C O H CH3 C CH3 CH3 C O H fomaldehyde benzaldehyde 2,2-dimethylpropanal acetophenone C O H C O H C O HH C O CH CH CH3 CH3 + Na+ -OH H -OH H C CH CH CH3 CH3 O- H C O H H2O H C O CH CH CH3 CH3CH OH H A reaction of a ketone, which does not readily undergo self-condensation, with an aromatic aldehyde, which cannot enolize, is a very useful and high yielding reaction. In this case, dehydration will be very favorable since the new double bond is conjugated with both the carbonyl group and with the benzene ring. docsity.com 11 Mixed aldol condensations in which a ketone reacts with an aromatic aldehyde are known as Claisen-Schmidt reactions. C O H Cl + CH3 C O CH2 Na+ -OH H -OH CH3 C CH2 O- C O H Cl CH3 C O CH COH2 H OH H -OH CH3 C O- CH CH OH CH3 C O CH CH Another way to ensure that only one of the condensation partners forms the enolate is to use LDA. This will convert the starting aldehyde or ketone rapidly and quantitatively to the enolate. The will ensure that this species acts as the nucleophile. A second aldehyde or ketone can then be added as the electrophile. CH3CH2 C O CH CH3 H LDA THF, low temp. -N[CHCH3)2] CH3CH2 C CH CH3 O- H C O CH2 CH3 CH3CH2 C O CH CH3 C CH2CH3H O- Li+ H3O+ CH3CH2 C O CH CH3 C CH2CH3H OH The Claisen Condensation of Two Esters As we mentioned, esters can also form enolates, though in smaller concentrations than aldehydes or ketones. These enolates can then react with unreacted starting material in a condensation reaction that is exactly analogous to the aldol reaction. This condensation reaction of esters is called the Claisen condensation, after the early German chemist, Ludwig Claisen, who developed the reaction. docsity.com 12 CH C O OCH3CH2CH3 Na+ -OCH3 HOCH3H -OCH3 CH C O- OCH3CH2CH3 CH2 C O O CH3CH2CH3 CH C O OCH3CH2CH3 C OCH3CH3CH2CH2 O- C C O OCH3CH2CH3 CCH3CH2CH2 O H -OCH3 C C O OCH3CH2CH3 CCH3CH2CH2 O- Work-up Add H3O+ C C O OCH3CH2CH3 CCH3CH2CH2 O H Final irreversible deprotonation of the now much more acidic α-proton (pKa 11) drives the equilibrium to the right. To isolate the neutral product the basic reaction mixture must be neutralized in the work-up. hemi-acetal, unstable through loss of -OCH3 In order for the reaction equilibrium to be favorable the starting ester must have two α−protons. The first is removed to make the enolate, which undergoes the condensation reaction, and the second is removed after the initial condensation. Once the β−ketoester intermediate forms, the α−proton is now much more acidic. It has a pKa of 11 versus a pKa ~25 for the starting ester. This final deprotonation is irreversible and is essential in driving the equilibrium in favor of the aldol product. Another important aspect of the Claisen condensation is that the base portion used must be the same as the alcohol portion of the ester. If aqueous sodium hydroxide is used, irreversible ester hydrolysis will be the predominant reaction pathway. CH2 C O OCH2CH3CH3 NaOH H2O-OH CH2 C O- OCH2CH3CH3 OH CH2 C O OCH3 H -OH CH2 C O O-CH3 But if sodium ethoxide is used we simply get an identity reaction. The ethoxide attacks the carbonyl carbon but the product of this reaction is simply the starting material. The other reaction that occurs is the Claisen condensation by means of enolate formation. docsity.com 15 C O CH3 + C O OCH3 1. NaOCH3 HOCH3 C O CH2 C O 2. H3O+ Only the ketone can enolize. This enolate then reacts with the methyl benzoate ester. The equilibrium is driven in the desired direction by final deprotonation of the acidic β−diketone. C O CH2 H -OCH3 C O- CH2 C O CH3O C O CH2 C O- OCH3 C O CH C O H -OCH3 C O- CH C OH3O+ C O CH2 C O We can also have intramolecular ring closure reactions between a ketone or aldehyde and an ester to form β−diketones. In the example below, several enolates are possible but the one that leads to a favorable five- or six-membered ring will lead to the predominant species. The proton next to the ketone or aldehyde will be removed faster to form the enolate than the proton next to the ester. CH2 C C OCH3 O O HA HB HC NaOCH3 Na+ -OCH3 CH2 C C OCH3 O HA HC O- Na+ -OCH3 CH2 C C OCH3 O O_ HA HB HOCH3CH3O- C C OCH3 O- O CH2 O O- OCH3 1 2 3 4 5 6 1 2 3 4 5 6 O O H -OCH3 -O O H3O+ O O H docsity.com 16 Again, three enolates are possible, HA, HB, HC, and all three will form in reversible reactions but only the enolate formed at HA will lead to a six-membered ring. The equilibrium is driven to the right by final deprotonation of the 1,3-diketone. To isolate the neutral product, the enolate must be neutralized with acid. Alkylation of Enolates We can alkylate enolates at the α-carbon by reaction with alkyl halides. To ensure that the alkylation reaction is the predominate pathway rather than the aldol reaction (when using aldehyde and ketones ) or the Claisen reaction (when using esters) it is best to use a strong, non-hindered base such as LDA to ensure that all of the starting carbonyl compound is converted to its enolate. This way there is no electrophilic carbonyl compound present and the desired electrophilic alkyl halide can be added. CH3CH2 C O CHCH3 H LDA THF low Temp. CH3CH2 C O- Li+ CHCH3 BrCH2CH2CH3 CH3CH2 C O CHCH3 CH2CH2CH3 With esters: O O H LDA THF low temp. (iPr)2N O O- Li+ Cl O O Alkylation of 1,3-dicarbonyl compounds occurs regioselectively at the more acidic position between the two carbonyl groups. CH2 C O CH C O CH3 Ha Hb pKa ~19 pKa ~11 Na+ -OCH3 HOCH3 CH3 C O- CH C O CH3 CH3CH2Br CH3 C O CH C O CH3 CH2CH3 Only the more acidic proton Hb is removed and protonoation occurs at C3. 1 2 3 4 5 β−ketoesters and 1,3-diesters react similarly. The Acetoacetic Ester Synthesis docsity.com 17 A very useful starting material for the synthesis of methyl ketone derivatives is to start with ethyl acetoacetate (an acetoacetic ester). The ethyl acetoacetate can be alkylated regioselectively at the carbon between the two carbonyls using a very mild base and then the activating ester group can be removed in a three-step sequence to give the ketone. CH3 C O CH C O OCH2CH3 ethyl acetoacetate H Na+ -OCH2CH3 HOCH2CH3-OEt CH3 C O- CH C O OCH2CH3 CH3CH2CH2Br CH3CH2CH2Br CH3 C O CH C O OCH2CH3 CH2CH2CH3 The β−ketoester can then be decarboxylated in a three-step sequence which involves (1) basic hydrolysis of the ester using aqueous sodium hydroxide (2) protonation on the carboxylate anion (3) and final heating. This sequence can all be carried in one reaction flask (“one pot”). CH3 C O CH C O OCH2CH3 CH2CH2CH3 Na+ -OH H2 CH3 C O CH C OCH2CH3 CH2CH2CH3 -O OH CH3 C O CH C CH2CH2CH3 O O H -OH CH3 C O CH C CH2CH2CH3 O O- H3O+CH3 C O CH C CH2CH2CH3 O OH Heat CH3 C O H C CH2CH2CH3 O O H CH3 C OH CH CH2CH2CH3 +O C O enol CH3 C O CH2CH2CH2CH3 ketone The acetoacetic ester can be dialkylated using two different alkylating agents. This is best done step-wise, adding one equivalent base and then the first alkylating agent, then adding the second equivalent of base followed by the second alkylating agent. docsity.com 20 compound that can be reversibly attached to a carboxylic acid derivative to control the direction of alkylation at the α−carbon and then removed when it is no longer needed. Many such chiral auxiliaries have been developed. One class of these compounds is based on the heterocyclic compound, 2-oxazolidinone. Chiral derivatives of 2-oxazoidinone can be prepared as single enantiomers from naturally occurring enantiomerically pure compounds. O NH O 2-oxazolidinone O NH O H CH3 HRS (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone The chiral auxiliary can be used in the synthesis of enantiomerically pure carboxylic acid derivatives such as (S)-2-methyl-4-pentenoic acid. Working backward from the product, it can be seen that it can be synthesized by alkylation of a propanoyl group with an allyl halide. HO O CH3H O- H CH3 + X enolate of a propanoyl group allyl halide (S)-2-methyl-4-pentenoic acid To control the stereochemistry, the chiral auxiliary was added first using propanoyl chloride and the chiral (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone to give a chiral amide. The enolate was form using LDA at low temperature. The carbonyl oxygen of the oxazolidinone coordinates the lithium counterion, forming a fairly rigid enolate structure. Attack on the allyl bromide electrophiles occurs from the side away from the large phenyl and methyl substituents on the oxazolidinone ring to give the (S) enantiomer as the major product. Hydrolysis of the chiral amide gives the desired carboxylic acid and the chiral auxiliary which can be recovered and reused. docsity.com 21 O NH O H CH3 H + Cl O O N O H CH3 H O LDA THF O N O H CH3 H O CH3 H Li Br The top face is sterically blocked by the -CH3 and phenyl groups so addition of the allyl group is from the bottom face. O N O H CH3 H O CH3H hydrolysisHO O CH3H O NH O H CH3 H + Enolzation and Enol Content Enols are the conjugate acids of enolates. Enolates, as we have seen are very useful in organic synthesis. Enols are generally present in very small concentration in equilibrium with the keto form. The keto form is more stable than the enol form by 45-60 KJ/mol (11- 14 Kcal/mol) because the C=O bond is more stable than the C=C bond of he enol. The enol and keto form are called tautomers. For normal esters, ketones and aldehydes, the enol form is present in very small amount amounts. CH3 C O OH CH2 C OH OH Keq ~ 10-20 acetic acid CH3 C O OCH3 CH2 C OCH3 OH Keq ~ 10-19 to 10-24 ethyl acetate CH3 C O CH3 CH2 C CH3 OH Keq 6 X 10-9 acetone docsity.com 22 CH3 C O H CH2 C H OH Keq 6 X 10-7 acetaldehyde CH C O H C C H OH Keq 1.4 X 10-4 CH3 CH3 2-methylpropanal CH3 CH3 CH3 C O CH2 C O OCH2CH3 CH3 O CH2CH3 OH O Keq 7 X 10-2 ethyl acetoacetate CH3 C O CH2 C O CH3 CH3 CH3 OH O Keq 2 X 10-1 2,4-pentandione For unsymmetrical ketones, enolization can occur on either side of the carbonyl and can result in E- or Z- stereoisomers. CH3 C O CH2 CH3 CH2 C OH CH2CH3 + CH3 C OH C CH3 H + CH3 C OH C H CH3 1-buten-2-ol (Z)-2-buten-2-ol (E)-2-buten-2-ol Esters and carboxylic acids contain less enol content than do aldehydes and ketones. This is due to electron donation to the carbonyl group by the oxygen. But for 1,3-dicarbonyl (β−dicarbonyl) the enol content is much higher. There are two main reasons for this: (1) The new double bond that is formed is conjugated with the carbonyl C=O bond. (2) There is intramolecular hydrogen-bonding of the enol OH group with the carbonyl oxygen. docsity.com 25 R C O CH3 + X2 NaOH H2O R C O O- + HCX3 The mechanism is shown below. Note that after the addition of the first iodine, the remaining two α-protons are slightly more acidic and after addition of the second iodine, the third α−proton is even more acidic. The –CI3 is a good leaving group and is displaced from the carbonyl carbon by hydroxide. This final step is irreversible, since the carbanion then removes a proton from the carboxylic acid. C O C H H H + -OH C O- C H H I2 I I C O C H I H HO- C O- C H I I I C O C H I I HO- C O- C I I I I C O C I I I HO- C O- CI3 OH C O O H C I I I + C O O- + H C I I I α−Halogenation of Carboxylic Acid (Hell-Volhard-Zelinsky Reaction) The α-proton next to the carbonyl carbon of a carboxylic acid can also be removed. Again, the enolate is involved but first the carboxylic acid halide is formed using a phosphorus trihalide reaction. Formation of the acid halide increases the acidity of the α- proton, making the enolate formation more favorable. After addition of the halide to the α−carbon, the acid halide is hydrolyzed back to the carboxylic acid during the work up. CH C O OHR H PX3 X2 CH C O XR X H2O CH C O OHR X docsity.com 26 CH C O OHCH3 H PBr3 Br2 CH C O BrCH3 H Br- CH C O- BrCH3 Br Br CH C O BrCH3 Br H2O CH C O OHCH3 Br This reaction is useful for making α−amino acid. CH C O OHCH H 1. PBr3, Br2 CH3 CH3 2. H2O CH C O OHCH Br CH3 CH3 NH3 H2O CH C O OHCH H2N CH3 CH3 +/- valine, an α−amino acid The α−proton can be replaced by deuterium to isotopically label a molecule. O + 4 D2O KOD heat H H H H O D D D D This occurs by means of the enolate. O H H H H -OD O- H H H D O D O D H H H repeat O D D D D Racemization of Chiral Carbonyl Compounds A chirality center that is next to a carbonyl group and has at least one α−proton is subject to racemization in either acidic or basic conditions. C O C CH2CH3 CH3 H pure (S) acid or base C O C CH2CH3 CH3 H C O C CH2CH3 H CH3 + 50% (s) 50% (R) docsity.com 27 In acidic conditions: An achiral enol intermediate forms reversible. This reverts back to starting ketone by means of reprotonation from hydronium ion (H3O+). The proton can add to either face, protonating from the top face to give the R-enantiomer or protonation from the bottom face to give the S-enantiomer. Both are equally likely and so after a period of time a solution of pure S-enantiomer will racemize into a 50:50 mixture of enantiomers. C O C CH2CH3 CH3 H H O H H C O C CH2CH3 CH3 H H H2O OH2 C O C CH3 CH2CH3 enol - achiral H OH2 H O H H top top face C O C CH2CH3 H CH3 bottom face H O H H C O C CH2CH3 CH3 H R-enantiomer S-enantiomer Basic conditions: C O C CH2CH3 CH3 H H2O -OH C O- C CH3 CH2CH3 achiral enolate H O H top face C O C CH2CH3 H CH3 50% R-enantiomerbottom face H O H C O C CH2CH3 CH3 H S-enantiomer Effects of Conjugation in α ,β−Unsaturated Aldehydes and Ketones When we have a double bond directly attached to a carbonyl group the double bond becomes electron deficient at the β−carbon. This is due to the electron withdrawing effect of the carbonyl group and is illustrated by drawing a resonance structure. docsity.com 30 C C C O H CH3 H H CH3O OCH3 O O H + Na+ -OCH3 HOCH3 -OCH3 CH3O OCH3 O- O C C C O H CH3 H H CH C O- H CH3 H C H CCCH3O O OCH3 O CH3OH CH2 CH C O H CH3 C H CCCH3O O OCH3 O In this case we can isolate the diester or we could decarboxylate one of them through the three-step sequence of (1) basic hydrolysis (2) protonation and (3) heating. CH2 CH C O H CH3 C H CCCH3O O OCH3 O 1. NaOH, H2O 2. H3O+ 3. heat CH2 CH C O H CH3 CH2CHO O We can use the Michael reaction to form new cyclic compounds by combining it with an intramolecular aldol reaction. This sequence is called the Robinson Annulation after Sir Robert Robinson who developed this reaction. He was awarded the Nobel Prize in 1918 for chemistry for his work. We start with a 1,3-dicarbonyl such as cyclohexane-1,3 – dione and methyl vinyl ketone or MVK. The most acidic site is the proton between the two carbonyl groups. The enolate forms there and attacks the β−carbon of methyl vinyl ketone. Removal of a proton at C1 forms an enolate that can undergo an intramolecular aldol reaction in the second phase of the reaction. Enolization can occur at other positions but again, the enolate that allows for formation of a five- or six-membered ring will be the predominant reaction pathway. docsity.com 31 O O Hb Hc + O CH2 H HH Ha Hb is activated by two carbonyl groups and it by far the most acidinc proton. It will be removed first. NaOH H2O OH pKa ~19 PKa ~19 pKa ~10 O O O CH3 H HH O O CH2 CH O CH3 H O H O O CH2 CH2 O CH2 H OH O O CH2 CH2 O CH2 O O H O H HO H OH O O 1 2 4 3 1234 docsity.com