carbonyl condensation

carbonyl condensation - SUMMARY CarbOnyl Condensation...

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Unformatted text preview: SUMMARY CarbOnyl Condensation Introduction to Carbonyl Condensation Reactions Carbonyl Condensation 1 Carbonyl Condensation Reactions 0 Condensation of Aldehydes and Ketones Carbonyl Condensation 2 0 Preparation of Enones via Dehydration of Aldols Carbonyl Condensation 3 0 Mixed Aldol Reactions Carbonyl Condensation 4 0 Preparation of B-Keto Esters via Claisen Condensation Carbonyl Condensation 5 0 Mixed Claisen Reactions Carbonyl Condensation 6 0 Michael Reaction Carbonyl Condensation 7 INTRODUCTION TO CARBONYL CONDENSATION REACTIONS Carbonyl Condensation 1 O 0 II NBOCH3CH3 1| 2 CHaCH \— CH3¢HCHZCH CH aCHEOH | Acetaldehyde 0" (aldehyde) 3—Hydr0xybutanol laldol] Keys: 1. 2. The reactants for this type of reaction are two carbOnyl compounds; one acts as a nucleophilic donor and the other as an electrophilic acceptor. The mechanism of this reaction can be viewed as a combination of nucleophilic addition and a-substitution reactions. From the perspective of the nucleophilic donor, this reaction is a simple tat-substitution reaction. Yet, from the perspective of the electrophilic acceptor, this is a nucleophilic addition reaction. . Many carbonyl compounds (e.g., aldehydes, ketones, esters, amides, acid anhydrides, thio esters, and nitriles) can undergo this type of condensation reaction. . The reaction is catalyzed by base (e.g., hydroxide, ethoxide). Mechanism: 1. The base (e.g., *OCHZCH3) abstracts an ot—proton from the first carbonyl compound to form an enolate ion intermediate which is stabilized by resonance. The resulting enolate ion is a nucleophilic donor. 2. The enolate ion then attacks the carbonyl carbon of the second carbonyl compound (electrophilic acceptor) to form a new C—C bond and an alkoxide ion. Notice that the first carbonyl compound (nucleophilic donor) has participated in an a—substitution reaction, replacing an cut-proton with a C—O‘ group. This reaction is very similar to the reaction of a Grignard reagent with an aldehyde or ketone; that is, the second carbonyl compound (electrophilic acceptor) undergoes a nucleophilic addition reaction. 3. The alkoxide ion abstracts a proton from an ethanol molecule to form the aldol condensation product and a molecule of base. CHSCHZOH 6.. r—:QCHZCH3 O H 0 .. o a ll: ('3 n" ® a ll (6? CH I f— _c_c'\ I /c\ n. R R'" R"" Enolate lst Carbonyl i0“ 2nd Carbonyl ® compound compound if r n .6 R—C—C—C—OZ H—O—CH2CH3 l E "\} I Rn Rm. Alkox1de Ethanol ion (3 . fi fit. FE... ‘ n—c—c—c—OH + 'OCHZCHa R” Rm. Base Aldo] INTRODUCTION TO CARBONYL CONDENSATION REACTIONS Carbonyl Condensation 1 0 0 II NaOCl—IgCHg : ll 2 CHaCH E CHJCHCHZCH CH3CH20H l Aeelaldehyde 0” (aldehyde) 3-Hydroxybutanol (aldol) Keys: 1. The reactants for this type of reaction are two carbonyl compounds; one acts as a nucleophilic donor and the other as an electrophilic acceptor. 2. The mechanism of this reaction can be viewed as a combination of nucleophilic addition and a—substitution reactions. From the perspective of the nucleophilic donor, this reaction is a simple u—substitution reaction. Yet, from the perspective of the electrophilic acceptor, this is a nucleophilic addition reaction. 3. Many carbonyl compounds (e.g., aldehydes, ketoues, esters, amides, acid anhydrides, thio esters, and nitriles) can undergo this type of condensation reaction. 4. The reaction is catalyzed by base (e.g., hydroxide, ethoxide). Mechanism: 1. The base (e.g., ‘OCHZCH3) abstracts an ot-proton from the first carbonyl compound to form an enolate ion intermediate which is stabilized by resonance. The resulting enolate ion is a nucleophilic donor. 2. The enolate ion then attacks the carbonyl carbon of the second carbonyl compound (electrophilic acceptor) to form a new C—C bond and an alkoxide ion. Notice that the first carbonyl compound (nucleophilic donor) has participated in an ct-substitution reaction, replacing an ot-proton with a C—O‘ group. This reaction is very similar to the reaction of a Grignard reagent with an aldehyde or ketonc; that is, the second carbonyl compound (electrophilic acceptor) undergoes a nucleophilic addition reaction. 3. The alkoxide ion abstracts a proton from an ethanol molecule to form the aldol condensation product and a molecule of base. CHacHon 8.. r—iQCHcha o H 0 .. 0 atta- ® “we” “:4 — — : '. \n' H'/" FI"" R Enolate lst Carbonyl i011 2nd Carbonyl ® compound compound ” T. Flt... n “G R—C—C—C—Ofi H—O—CH CH | | "\J 2 3 , H" H"" Alkomde Ethanol ion ® 0 R. R... ‘ il l | HACA?7?70H + 'OCH20H3 3.. R.... Aldo] Base PREPARATION OF ALDOLS Carbonyl Condensation 2 VIA CONDENSATION OF ALDEHYDES O OH H O H NaOCHECHi I I II 2 CflacHz—CH .x—.—\ Cchch—C—CH CH3CH10H I I Propanal H CH3 (aldehyde) 2-Melhyl-3-hydroxypcntanal (aldol) Keys: 1. This is a carbonyl condensation reaction in which two identical aldehydes combine to form an aldol prod- uct. Aldols, as the name implies, have two functional groups: an aldehyde group (ald) and a hydroxyl group (01) attached to the [i-carbon of the aldehyde (see Carbonyl a—Substitution 1 for the definition of a [3- carbon). . Similar to other carbonyl condensation reactions, this reaction occurs rapidly and is completely reversible. . This reaction can be broken down into two stages: a. Generation of an enolate ion intermediate from the first aldehyde compound; this step is catalyzed by bases such as NaOH. b. Addition of the enolate ion to the second aldehyde compound in a nucleophilic addition reaction to form a tetrahedral ion intermediate, which subsequently becomes protonated to yield the aldol product. 4. It is important to know that the aldehyde reagents must have at least One (ii-proton; otherwise this reaction will not occur. Reason: The base can abstract protons only from the ot-carbon to form an enolate ion inter- mediate; protons on other carbons are much less acidic than or-protons. 5. At equilibrium, aldol products are favored whenever monosubstituted aldehydes (RCHZCHO) are used as reagents. If disubstituted aldehydes (RZCHCHO) are used as reagents, the equilibrium shifts to favor the starting materials {mainly for steric'reasons). For this same reason, most ketones are not good candidates for this reaction. However, conversion of ketones to aldols is possible. ' DJN Notes: 1. Intramolecular aldol reaction: This reaction occurs when the starting compound has both the nucleophilic donor and the electrophilic acceptor in the same molecule. It readily occurs if the reaction produces a five- or six-carbon ring in the product molecule because there is very little ring strain. The mechanism of this reaction is very similar to that of the aldol reaction involving two identical aldehydes. CHO 0 NaOH EH H‘O% ( See Carbonyl ) CHO 2 d l' 3 H C0“ ensa lull | f 0" -._— H ck‘o Hexanedial Aldo] product miS-Unsaturated aldehyde (aldehyde) 2. Reactions involving ketones are similar to those of aldehydes. Mechanism: 1. The base (ethoxide ion) abstracts one HOCHch: H OL-proton from the first aldehyde to egfimzcm <1? I I form an enolate ion intermediate, 0 H‘ (base) 0 "_c_‘f‘R which is stabilized by resonance. H_{|;_(|:2R H_g_§g:R\J H 2. The nucleophilic enolate ion attacks I : (13 | 2nd Ald‘fl‘yde the carbonyl carbon of the second H Enamel“ aldehyde to form a new C—C bond 1"" Aldehydc ® and an alkox1de Ion. I I /‘H_°_CH2CH3 3. Protonatlon of the alkOXIde lOI‘l by (I? ‘3 (RH [v Q) C", ['1 g??? V ethanol ylelds the aldol product and OCHZCHa + H_C_C_C_C_H. ; H_c_c_c_c_n. regenerates the base catalyst. l l l : | | | Base H H H ‘ H H H Aldol Alkoxide ion (tetrahedral intermediate) PREPARATION OF CONJUGATED EN ONES CarbOnyl Condensation 3 VIA DEHYDRATION OF ALDOL PRODUCTS (ALDOL CONDENSATION) 0 CH3 OH O CH3H II I | H®w90H II I | CHJ—c-cieicua —> CHa—C—C=c—-CH3 + H20 H H 3-Methyl-3-penten-2-one 4-Hydroxy-3—methyi-2-pemanone (enema) (aidol product) Law 1. This reaction converts aldol products {B—hydroxy'aldehydes or ketones) to conjugated enones (afi- nnsaturated aldehydes or ketones). 2. The reaction can be catalyzed by either an acid or a base: a. The acid—catalyzed reaction proceeds by the usual E2. mechanism. b. In base—catalyzed aldol dehydration, the reaction proceeds through an enolate ion intermediate. It is important to remember that alcohols cannot be dehydrated by a base under normal conditions. Note: Conjugated enones are more stable than unconjugated ones because the former have partial delocalization of electrons over all four pi—bonded atoms (i.e., resonance stabilization), while the latter do not. H | Resonance I | o Conjugated enone Mechanism: Base-catalyzed 1. The base abstracts an (Jr-proton from an aldol condensation product, thereby forming a resonance- stabilized enolate ion intermediate. 2. The anion (e.g., enolare form A or B) expels the B-hydroxyl group to form a double bond. The product is a conjugated enone. “6 0 Fl' OH O H' OH :0: H' OH F. (I; e s; who a l: 93% 5% a}; l | e’UI U1 H R... R... m Aldo] k—e:'§m FonnA Form B enolale ion enolate ion (2) O n' ,, II l f‘ e H—C—C=C\ + OH + H20 R... Enone Acid-catalyzed 1. The oxygen atom of the aldol hydroxyl group is protonated by an acid (e.g., hydronium ion). 2. A base (e.g., water) causes an E2 elimination reaction: An (Jr-proton and the protonated hydroxyl group are eliminated simultaneously to form a double bond. 6) Hip—H F a - a o H':'dH o R‘ H2 0 R' H“ 1 H—cIl—c:;—+—n" $ n—g—cizje—H" {afiz R—cli—tlz=c< + H20 + Hao+ H Rm (TH Hm Enone Hm Aldo] /§\ MIXED ALDOL REACTIONS Carbonyl Condensation 4 0H; 0 5 OH H o r .......... .—, NaOH | i II E | l H CH30H2CH20HO + —> CHacchchl—LEIIEEEJ + CHgfli—(II—CH Butanal Acelaldehyde H H CHacHa (aldehyde) (aldehyde) 3-Hydroxyhexanal 27Elhyl~3-hydroxybutanal (aldol) (aldoi) Keys: 1. This aldol reaction involves two nonidentical carbonyl compounds. Both compounds must be able to act either as a nucleophilic donor or an electrophilic acceptor. 2. This reaction also occurs in two stages: a. The first carbonyl compound is converted to an enolate ion intermediate; this step is catalyzed by bases such as NaOH. b. The enolate ion attacks the second carbonyl compound in a nucleophilic reaction to form a tetrahedral intermediate which subsequently becomes protonated to yield the aldol product. 3. Because the carbonyl compounds are not identical, mixtures of aldol products are generated with this reac— tion. The accompanying table illustrates the different types of products that can be generated from this reaction. Mixed Aldol Reaction (A + B) Nucleophilic Donor Electrophilic Acceptor Product A . A AA (symmetric) B B BB (symmetaic) A B AB (asymmetric) B A BA (asymmetric) “A and B represent non-identical carbonyl compounds. 4. The mixture of products can be avoided under the following situations: a. One of the carbonyl compounds has no wproton and thus can only be the electrophilic acceptor (e.g., formaldehyde, benzaldehyde), and one of the carbonyl compounds is a nucleophilic donor because it can form an enolate ion. , _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ . _ . . . _ . _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _. o i 0 0H §H o y 5 CH CH (I‘iCH CH 5 ll ———>J\IEOCHECH3 H (I: :(I: ii CH CH l I I + _ _; _ _ L ____ H/ \H CHBCHZOH I ! 2 a E H ;cIH3 : 3-Pentanone Formaldehyde """""""""""" " (kemne) {aldehyde} 5-Hydroxy74imethyli3ipenlanone (aldol) b. Or one of the carbonyl compounds (e.g., ethyl acetoacetate) is much more acidic than the other (e.g., acetone). 0 o o o H o n d R on (lien iiOCH CH NaOCHECH" eH ii (I: lice" CH _ _ ‘ % _ _ + 3 2 2 : CHRCHEOH 3 l 2 a Ketone Ethyl aceloacetate R7 (IiiFl' OH Aldo] Mechanism: q 1. The base (OH_) takes an ot~proton from z?” H the aldehyde or ketone to make a [650- lawman“: R_c=c< Hence-stabilized enolate anion. Note that formaldehyde has no oc-proton to be abstracted. 2. Nucleophilic attack on the formaldehyde by the enolate anion forms an alkoxide ion. 9" (a. 3. The alkoxide ion abstracts a proton from 0 H 3 0 Ell T fifliocmcm an alcohol solvent, producing the aldol SR-c—c—1e—n 4; n—c—e—c—H Alcohol product. l l I I I Formaldehyde __________ H H H Adol . (Note that only a single product is formed + Allows because one of the conditions described in figcflzcfla m Keys, item 4, has been fulfilled.) PREPARATION OF B-KETO ESTERS Carbonyl Condensation 5 VIA ACETOACETIC ESTER (CLAISEN CONDENSATION) o o cngo ll l)Na0CH3CH3/CH3CH20H ll I II 2 CH3CH2COCHZCH3 W era—cure—rlz—cocnzcma 3 Ethyl propanoalc H (ester) ElhyI-2-mclhyl-3-oxopenmnoate (B-keto ester) Keys: 1. This reaction converts two molecules of ester to one molecule of B-keto ester. 2. The reaction involves the conversion of one ester molecule to an enolate ion intermediate via a base cata- lyst, followed by a nucleophilic addition reaction between the enolate ion and the second ester molecule to form a tetrahedral ion intermediate. 3. The reaction sequence is very similar to that of the aldol synthesis reaction (see Carbonyl Condensation 2). The major difference is that the tetrahedral intermediate in the Claisen reaction expels the alkoxide ion group (see Mechanism, step 3) instead of being protonated as in the aldol synthesis. Note: An intramolecular Claisen condensation (Dieckmann cyclization) takes place when a single linear compound has two ester groups. The product is a Cyclic compound. The reaction works best when 1,6-diesters or 1,7- diesters are used as the starting esters, forming five- or six-membered ring products, respectively. This mecha- nism is the same as that for the Claisen condensation reaction. 0L . o ('3'! ocnzcna 1) NaOCHzCH3 I CH3CH20H ficoc'fic’h a y H /0 2) HJo+ OCHgCHa Dielhyl hexanedioale Ethyl (2-0xocyclopentane) carboxylale di-esler cycloketone ester Mechanism: 1. 4:93 The base (—0R) abstracts an ot-proton from the first ester to generate an ester enolate ion which is stabi- lized by resonance. . The nucleophilic ester enolate ion attacks the carbonyl carbon of the second ester to produce a tetrahedral anion intermediate. . This newly formed anion intermediate is unstable and expels an alkoxide group to form the B-keto ester. . The reaction does not end at this point. The expelled alkoxide ion is basic, and it abstracts an oc—proton from the initial [S-keto ester product to form a very stable enolate ion. This is the key step that drives the equilibrium of this reaction toward the product side. . Addition of acid to the enolate ion forms the final B-keto ester product. Fl 0 | H3 H’C’C’OR' | 2ndEiter H A fit (H) FIOH F“ $1, :5?” a H—C—C—OR :c—c—on'4—> \c=c—on ! f El Resonance H/ (’H Ester H Enolaleinn ': 2-3 H :0: H J: :30. I UR H E R—f—(‘f—OR' H O Telrahedral intermediate , rs OFl' "D Tl??? Milli *Hio" Hill (5‘, as) H-"C C C COR'i H C C C Con H’C’C’CAC—OH' J. l H? .L 7 I “I 2 a H H , B—Kelo ester £11013“: 10“ H_?_ H BiKeto ester H Base PREPARATION OF B-KETO ESTERS Carbonyl Condensation 6 VIA MIXED CIAISEN CONDENSATION REACTION 0 O I O O )I H CH H II Fl CH3 + cmcocsz W @— c —CH1cocuchg + CH30H 3 + Methyl benzoate Ethylacetale Ethyl benzoylacetate Methanol (electron acceptor) (electron donor) (B-keto ester) (alcohol) CSICI’ ester Keys: 1. Overall, this Claisen reaction is very similar to the last reaction (see Carbonyl Condensation 5). The only difference is that this reaction uses two nonidentical esters. Hence, a mixture of B-keto ester products may be generated {see Carbonyl Condensation 4 for details on mixed aldol products). 2.. Product mixture can be avoided if one of the ester compounds has no (it-proton (see sample reaction). Reason: An ester without an ot—proton can act only as an electrophilic acceptor. Note: Esters and ketones can also form B-diketones in a mixed Claisenrlike reaction in which the ester has no ot- protons. Mechanism: 1. The base (‘OC2H5) abstracts an ot-proton from the ester to generate an ester enolate ion. 2. The nucleophilic ester enolate ion attacks the carbonyl carbon atom of the second ester (alkyl formate) to produce a tetrahedral anion intermediate. Note that the alkyl formate has no ot-proton to be abstracted. Thus, it can be only an electrophilic acceptor. 3. This newly formed anion intermediate is unstable and expels an alkoxide group to form the B—keto ester. 4. The reaction does not end at this point. The expelled alkoxide ion is basic, and it abstracrs an (Jr-proton from the initial B-keto ester product to form a highly stabilized enolate ion. This is the key step that drives the equilibrium of this reaction toward the product side. 5. Addition of acid to the enolate ion forms the final B-keto ester product. (Note that in the above mechanism, only a single product is formed because the condition described in Keys, item 2, has been fulfilled.) o u) H—C—OR" 2ndEster T i? - T if w It”)? ‘1? r1) 9 ' H—[ijCOR' “i :c—con- H—ereicon' I . | H Em” H on" H CHSCHafiig Emma“: ‘0“ Tetrahedral intermediate Base ‘ Son" =3) 0 Ft' 0 o H o o n o Hiitic‘ion' Hiicliion'AE—Hiieiion' \ v7 _7 CI g H H20 g Q Enolate K . B—Kelo ester B—Keto ester "TR—H i0" edeHch; H Base MICHAEL REACTION Carbonyl Condensation 7 5 o 5 o o 1) NaOCHZCHJI o 5 o E ll 5 li il CH3CH20H il i Ii : E H2C = CHCCHZCHJ E + CHJCHzOC '— CHZCOCHchg ’2)H0+—> CHacHQOCCI'JHiCHZCHZCCchHa F ' ........................... ..‘ 3 _______________________ .r 4-Penten-3-one Diethyl malonate EOCH2CH3 (enone) (maionic ester) 0 Michael reaction product Keys: 1. The reaction takes place between an (LB-unsaturated carbonyl compound (e.g., a conjugated aldehyde, ester, ketone, or amide} and an enolate ion (see Mechanism for details). 2. The enolate ion acts as a nucleophilic donor, and the a,B~unsaturated carbonyl compound as an elec- trophilic acceptor. 3. A high-yield product can be generated when a stable enolate ion (i.e., one derived from malonic ester or B— keto ester) reacts with a sterically unhindered Dob-unsaturated ketone. 4. The enolate ion can be generated from B-keto esters, malonic esters, and B-keto nitriles. Notes: 1. Preparation of a S-keto acid from Michael products. E o H H i con' 0 o H H o E II I | E | 1| l]KOH,CH1CHgOH || | | Ii gH—c—c—c+c—con' -——~—'—> n—c—c—c— CHZCOH E i i E i 2) H+ 1 I l .......... ,l'l,,,fl,l H 3) Heat H H Michael addition BwKeto acid product. 2. The Robinson annulation reaction takes place in a two-step process involving a Michael reaction and an intramolecular aldol reaction. Note that a cyclohexenone product is formed. CH2 a cage": H H cozcfl3 l) NaOCHgCHgl' CH3CH20H coch:l ' l) NaOL H3(.HngH3CH30H 2 Aldol reaction + + H20 via Michael reaction / 0 CH3 0 0H3 0 0 0 CH3 Kctonc Acetoacelule Michael Annulution addition product product Mechanism: 1. The base catalyst abstracts an (I-proton from the B-keto ester to form an enolate ion. 2. The nucleophilic enolate ion attacks the B-carbon of the ot,B-unsaturated ketone to form a new enolate ion. 3. The newly formed enolate ion abstracts a proton from solvent to form the Michael addition product and regenerate the base catalyst. 4. The intermediate Michael addition product then undergoes a} an intramolecular aldol condensation (see Carbonyl Condensation 4), followed by b) a dehydration reaction (see Carbonyl Condensation 3). i T i m “f” if 7' if H if .1, \ H082C7CH' f HOC—-§\:CH/‘/C=c—C—H |. a H A H m BiKeto ester quftc OLE-Unsaturated :9“ @- kctune Base catalyst i' 7‘ i" irnii H9: ii 'i 'i imii Roe—c—c—e—c—H _/, Roc—c—ejgg—cn . fin‘ H H Itltw H a o o RCQH Michael Product Enolale A Icoho] ion ...
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This note was uploaded on 09/13/2009 for the course CHEM 12-636 taught by Professor Hubbard during the Spring '09 term at UGA.

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carbonyl condensation - SUMMARY CarbOnyl Condensation...

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