<<

Reactions involving carbonyl compounds Chapter Introduction The reactions of carbonyl compounds are one of the most important class of synthetically useful reaction in organic . The carbonyl functional group is also regarded as the most important functional group. This functional group can participate in multiple modes of reactions. The reactions of carbonyls can be broadly classified as the direct reactions wherein a adds to the carbonyl atom. The other equally important and versatile family of reactions of carbonyl arise due to the acidity of the alpha-C-H groups. Upon treatment with a , such compounds are capable of yielding a very useful nucloeophile, known as . The chemistry of are widely exploited for the generation of C- C bonds in various reaction. This module is therefore very important for the practice of and its mechanisms. I. Nucleophilic addition reactions of , , carboxylic , etc., a very common of all functional Introduction groups in , shows most important and simplest of all reactions i.e. nucleophilic addition.

O NaCN, H SO Addition of to 2 4 CN H2O C acetone gives acetone OH . Reaction proceeds in two steps. In first step nucleophilic addition of cyanide occurs followed by a of the resulting anion. In fact, this is general feature of all nucleophilic of carbonyl compound. Mechanism of nucleophilic addition H-CN O CN O NC OH + CN

CN

Reactivity of carbonyl Orbital considerations give a clear picture of these group towards addition reactions. C=O of carbonyl compounds is sp2 hybridized and is planar. It has shorter bond length than typical C-O and is twice strong than C-O. What makes it reactive toward addition reaction is polarization of C=O bond. ( of C is 2.5 while that of O is 3.5 ) Polarization makes carbon partially positive which encourages addition of negatively charged cyanide . Orbital considerations: Why carbonyl groups are ?

O 2.5 3.5 C O δ+ δ

The C-O bond is polarized towards the more electronegative

Bonding in carbonyl group

LUMO Unfilled orbital

Filled orbital HOMO When nucleophile adds to carbonyl group, its HOMO reacts with LUMO of carbonyl group. So when this LUMO is more polarized i.e., coefficient of LUMO at carbon is greater, then Complete diagram of filled this interaction is better. orbitals of carbonyl compounds

When the HOMO of a nucleophile interacts with the LUMO of a carbonyl group, a new σ bond is formed and π bond is broken due to filling of electrons to the antibonding π* orbital of carbonyl group. Electrons from HOMO of nucleophile now migrate towards oxygen giving it negative charge. new σ bond is formed at expense of π bond.

O OH Cyanohydrin formed from CN this cyclic ketone is used in NaCN, H2O syntheses of 5HT agonists. N 3 N

The reaction is facilited by acid catalyst and is in equilibrium with starting material. Hence only reaction favoring product will give good yield. O CN can also be Me3SiCN obtained from addition of 1 mol% cat OSiMe3 24h trimethylsilylcyanide. F C F3C 3 100% (56% ee)

Bolokon,Y.N; Green,B; tBu tBu Ikonnikov, N.S; North,M; Parsons,T; Tararov,V.I; Tet. Lett., 2001, 57, 771. tBu tBu N O O N O Ti Ti Catalyst : O N O O N tBu tBu

tBu tBu Reaction of organometallic compound with (A). Reactions with organometallic compounds carbonyl compound is a very important reaction as it gives by C-C bond formation. (A.1) Lithium and Lithium and containing magnesium in nucleophilic organometallic compounds are of importance in addition reaction these reactions. Lithium and magnesium are very electropositive metals and hence electron density is highly polarized towards carbon in these reagents. Hence, making them good nucleophiles which attack carbonyl compounds.

O OH Reaction of 1.MeLi, THF 2. H O 2 H with aldehyde R H R Mechanism is similar to typical nucleophilic addition reaction. OH O O Me Li H OH

H H R H R R Orbital diagram gives clear picture of reaction.

Orbitals involved in addition of methyllithium

In these reactions, is added in last step of reaction, after methyllithium is added to carbonyl compound. Organolithium or organomagnesium compounds are very reactive towards water and react readily to give . To avoid this kind of side reaction, reaction is carried out in presence of aprotic like

THF, Et2O etc.,

Buhler,J.L, JOC, 1973, 38, nBu O nBuLi 904. hexane OH -780C

98% O OH

Maruoka,K; Nonoshita,K; MeLi MAD Yamamoto,H; Tet. Lett., 1987, 28, 5723. -780C

Catalyst for reaction 77% MAD- Methylaluminiumbis(2,6- tBu tBu ditert.butyl-4- Me O O Me methylphenoxide) Al

tBu Me tBu Organomagnesium reagents are known as and these class of compounds also react in same way as that of organomagnesium and organolithium compounds.

O OH Reaction of Grignard’s 1.PhMgBr, Et2O reagent with carbonyl 2. H2O H compound R H R

Product of reaction of Grignard’s reagent with carbonyl compound and that of analogous organolithium compound is same.

Victor Grignard is the name of a German scientist. Pronounced as “Grini-yard” Addition of Grignard Reagents [carbon nucleophiles] Grignard reagents are strong bases as well as nucleophiles These compounds can be used for C-C bond formation reactions (construction of organic )

O OH 1. RMgBr 2. H O+ 3 R R1 H R1 H

H

O H H Br MgBr O Mg O OH R R R R1 H R1 R1 H H

Aldehyde sec- Addition of Grignard Reagents Grignard reagents and add to a range of carbonyl compounds,

OH RMgBr CO2 O C O O R

O OH RMgBr Formaldehyde p-alcohol R H H H H

O OH Aldehyde RMgBr sec-alcohol R R1 H R1 H

O OH Ketone RMgBr tert-alcohol R R1 R2 R1 R2 Formaldehyde on reaction with Grignard’s reagent gives whereas other give secondary alcohol and give tertiary alcohols. [More examples]

O MgBr Formation of primary 1.Et2O OH alcohol + H H 2.H3O

Formation of secondary O OH 1.EtMgBr, Et2O alcohol H 2.H2O, H

O 1.EtMgBr, Et2O Formation of tertiary 2.aq. NH4Cl alcohol OH More examples

In presence of strong acid, elimination product is obtained.

O OH 1.MeMgI Reaction of with 2.HCl methylmagnesiumbromide

O THF Use of alkylmagnesiumate in -780C + EtMe MgLi Grignard’s type reaction 2 5h

Manabu,H; Tokihiko, M; HO Et HO Me Kazuak,I; Org.Lett., 2005, 7,

573. +

89% 7% (A.2) Reformatsky In Reformatsky reaction, aldehydes and ketones reaction on treatment with α-haloesters in presence of metallic zinc give β-hydroxyester.

O C COOEt General reaction for Zn H2O + C COOEt Reformatsky reaction C Br OZnBr

C COOEt

C

OH

Reaction goes through intermediate analogous to Grignard’s reagent. Reaction may, particularly, in case of aldehydes produce olefin by elimination. Reaction of benzaldehyde CHO Br 1.Zn 2.H3O with + Ethyl 2-bromopropionate COOEt

-H2O COOEt COOEt OH

Organozinc reagents are less reactive than Grignard reagent or organolithium reagents. Thus, they do not react with and substitution product may result instead.

O Zn C COOEt + C COOEt R OR1 C Br R O More examples Reaction of benzaldehyde CHO Ph with BrCH2COOtBu / Zn COOtBu THF, 00C t-butyl 2-bromoethanoate H OH 90% (62% ee)

O O Zn, THF + OMe 600C

MeO Br OMe

HO OMe O HCl, THF rt, 10h O

MeO MeO 92% Water and alcohol, when added to carbonyl (B). Hydration and hemiacetal formation compound, behave as nucleophiles and add to them giving corresponding hydrates and hemiacetals or hemiketal respectively.

Hydration O HO OH H2O

1 R R1 R R

Hemiacetal formation O EtOH, H HO OEt

R R1 R R1 Reaction is in equilibrium and position of equilibrium depends upon nature of carbonyl compound. Formaldehyde reacts readily than any other carbonyl compound and exists mostly in hydrate form in water. Formaldehyde is present in O HO OH hydrated form in aqueous H2O, H solution H H H H

Mechanism for hydration/ Cl formation (example given is for acetal H OH formation) O + Cl H Water is a weak nucleophile and hence H ROH activation of carbonyl by way of protonation is required for effective addition of water. RO OH RO H OH + HCl H H

Hydration of chloral is favorable reaction and most of chloral is in O OH hydrated form. H2O Cl C OH Cl3C H 3 H O O

OH H2O O OH

O O

Mechanism for hemiacetal formation follows same route. It is called hemiacetal because it is halfway to acetal. When carbonyl and are present Intramolecular hemiacetal formation reaction within same , intramolecular reaction occurs to give cyclic hemiacetal.

O O Reaction of OH HO 4-hydroxybutyraldehyde H H gives cyclic hemiacetal

O O O OH O Hydroxyketones can also P Ph P Ph form cyclic hemiacetals O Ph Ph OH O HO HO OH O O HO HO HO HO OH OH OH (>99%) Glucose and ribose mainly exists in cyclic hemiacetal form OH O O OH HO HO HO OH HO OH ribose C. Addition of [amines as nucleophiles] Carbonyl compounds such as aldehydes and ketones can react with derivatives

Nature of Name of the product Structure

R p-amine (Schiff bases) N

NR2 sec-amine Enamine

OH hydroxylamine Oxime N

NH2 hydrazone N Condensation reactions with ammonia derivatives Condensation reactions* with ammonia derivatives lead to Schiff bases

Addition Tetrahedral Elimination intermediate

Acid catalyzed

R O RHN OH N + HOH

RNH2 Carbinolamine Imine

* One or more molecules are joined with the loss of water or another small molecules C.1. Condensation reactions with ammonia derivatives Generation of Enamines

HO O R2N CH3 -H2O CH3 R2N CH3 H3C H3C H C R2NH 3 H H 2°-Carbinolamine Enamine

Secondary amines can give enamines upon condensation with ketones

O N H+ + N H

Enamines are very good nucleophiles for C-C bond formation D. The Wittig Reaction [ as nucleophiles]

Georg Wittig (1954): Nobel prize winner 1979 Reactions of aldehydes or ketones with phosphorous * to give

R3 R R3 1 C Ph3P CR1R2 + C O C + Ph3P O R R 4 4 R2

Phosphorous stabilized carbanions

Ph3P CR1R2 Ph3P CR1R2 Due to character ylidic are highly nucleophilic ylene

* Ylides are neutral molecules with a negatively charged carbon atom and a positively charged heteroatom (P, S, N etc.,) Mechanism of Wittig Reaction

O Ph3P O Ph3P O

R3 R4 R1 C C R3 R1 C C R3 Ph3P CR1R2 R 2 R4 R2 R4 Betaine Oxaphosphetan e

R1 R3

C C + Ph3P O

R2 R4

Phosphine oxide is a very stable species. Formation of alkene as well as oxide provides great thermodyanic drive for this reaction Wittig Reaction is an olefination reaction

O CH2 Ph P + Ph3P CH2 + 3 O

Choice of R2CX is critical while planning a Wittig olefination reaction

C CR2

Br

Ph P R C Br Ph3P CR2 Ph3P CR2 3 2

H H

Bu Li

Other bases used for the generation of ylides: t-BuOK, NaH Carbonyl compound containing α- II. Reaction of enolates atom, when reacted with base, loses its acidic proton and forms an enolate.

O O OH Formation of enolate ion H R R Enolate ion is an alkoxide ion but is more stable to that of corresponding form because it is a conjugated, three atom, four electron system. Delocalization of enolate O O ion R R

Charge is mainly on oxygen atom, more electronegative atom. Same can be shown by use of orbitals involved. Populated π orbital of enolate ion

In enolate, thus, more of negative charge is on oxygen and the HOMO is centered more on the carbon atom. Various reactions are shown to proceed via enolate ion formation. is a self condensation II. (A). Aldol condensation reaction between molecules containing α- hydrogen atom in presence of base. The product of reaction is a β-hydroxy carbonyl compound.

Base catalyzed Aldol O O OH O OH condensation of + acetaldehyde H H H Mechanism for Aldol condensation O O Base first abstracts proton + from carbonyl compound H H and gives enolate which HO H then adds to other molecule O O OH O -OH of carbonyl compound to give β–hydroxycarbonyl H H compound Reaction is also furnished by ketones.

O O O OH HO Base catalyzed Aldol + condensation of acetone

In high basic conditions, further reaction occur i.e. elimination.

O OH -H2O O OH Elimination of water molecule proceeds via O E1cB mechanism In case of symmetrical carbonyl compound, which way enolisation occurs is unimportant. Similarly, in case of unsymmetrical carbonyl compounds, containing only one α-hydrogen atom, which way it is enolized is unquestionable.

O HO O

Base catalyzed Aldol OH condensation of acetophenone

In acetophenone, only methyl protons can be enolized. Similarly, in case of , only methylene protons are available for enolisation. O O Base catalyzed Aldol 1. HO O 2. -H O O O condensation of cyclic ester 2

Aldol reactions can also be furnished using specific enol equivalent, such as, lithium or silyl enol etc. O OLi using LDA lithium enolate THF -780C

O OLi O OH H

82% Aldol reaction using silyl O OSiMe3 enol ether Me3SiCl Et3N

Reaction of O 2-methylbutyraldehde with OSiMe3 H O of

3-pentanone 1. TiCl4 2. TsOH

When two different carbonyl compound are treated with base, condensation is observed, similar to that of self condensation. This reaction is known as cross-aldol condensation. O O

+H NaOH H2O / EtOH Cross-Aldol reaction NO2 between acetophenone and O 4-nitrobenzaldehyde

NO2

For these kind of reactions to work, there must be present at least one component which can not be enolized and is electrophilic enough for nucleophilic attack to occur and other component must be enolizable. When, in a molecule present, two carbonyl functional groups such that one can be enolized and other is electrophilic, intramolecular Aldol reaction takes place.

O O Intramolecular Aldol reaction of 1,6-diketone base

O O O O

-H2O

OH ~100% In case of unsymmetrical diketones, there are four different sites for enolisation and the final product depends on whether reaction is kinetically controlled or thermodynamically controlled.

O Intramolecular Aldol KOH O reaction of 1,5-diketone

O 90%

In this reaction, though there are several possibilities of inter and intra molecular condensation, only this product is formed in 90% yield. This is because it leads to stable conjugated enone in six membered ring. O KOH

Intramolecular Aldol O reaction of 1,4-diketone O

80%

In this reaction, 80% of the product, cis- jasmone is formed, as reaction is under thermodynamic control. Knoevenagel reaction is modified aldol II. (B). Knoevenagel reaction reaction, in which reaction of carbonyl compound with active methylene compound, proceeds through enolate formation, in presence of weakly basic conditions.

O O O COOEt base + R R H EtO OEt COOEt

Active methylene compound in the reaction can be diethylmalonate, ethylacetoacetate, malonic acid, Meldrum’s acid, cyanoacetic ester etc. Weakly basic conditions can be maintained by use of or piperidine in reaction. Mechanism is as follows. O O Attack of base on active O O methylene compound to EtO OEt EtO OEt give enolate H H R2NH

O O of O O enolate to carbonyl EtO OEt EtO OEt compound H O H OH R O R O O O O

Removal of water molecule EtO OEt EtO OEt H by E1cB mechanism to HNR2 give final product R OH R OH O O

EtO OEt

R Few more examples of Knoevenagel reaction

CHO

ethylammonium CN nitrate, rt, 10h + COOEt EtOOC CN 87%

O O O pH 7.8 H O COOEt + 2 400C H 4h 86% Kourouli, T; Kefalas, P; Ragoussis, N; Ragoussis, V, JOC, 2002, 67, 4615 II. (C). Perkin reaction Reaction of acid anhydride and aromatic aldehyde in presence of strong base, is Perkin reaction.

O O CH COO + PhCHO 3 COOH Ph O

Mechanism of reaction O O O O + AcOH Formation of enolate of H O O anhydride AcO

O O O O O O Aldol type addition of enolate to carbonyl O Ph H O Ph compound O Intramolecular acylation O followed by loss of O O O O

O Ph Ph O

In next step mixed Ac2O O O anhydride formed by O O O O addition of acetic COO Ph O anhydride loses Ph and is hydrolyzed in single step to give unsaturated O O O O acid AcOH COOH Ph Ph O

H AcO Mechanism is supported by fact that, when anhydride containing no enolizable protons is used, then final product of the reaction is one corresponding to the one obtained by loss of carboxylate.

O2N CHO + MeO CH2COOH

pyridine Ketcham, R, J. Chem. (CH3CO)2O Educ., 1964, 41, 565 30 min

HOOC OMe

O2N

trans= 82% & cis= 10% More examples

HOOC CHO

NEt3, Ac2O Gaukroger, K; Hadfield, + J.A; Hepworth, L.A; OH MeO OMe Lawrence, N.J; McGown, OMe A.T, JOC, 2001, 66, 8135 OMe HOOC OH

OMe

MeO OMe

OMe 60% Self condensation reaction of enolizable ester, in II. (D). the presence of base, is Claisen condensation. O O O Ethylacetate on reaction NaOEt with sodiumethoxide gives OEt OEt ethylacetoacetate. O O H Mechanism of reaction EtO OEt OEt

O O O OEt O

OEt OEt OEt

O O

OEt Mechanism is similar to that of Aldol condensation. In this reaction, first ester is enolized. It then attacks another molecule of ester in the same way as that in aldol condensation. Adduct of the reaction then loses ethoxide, as it is good . Product of the reaction is β-ketoester.

O O O tBuOK, 900C Ph Ph solvent free, OBn OBn 20 min Ph 84%

Cross-Claisen condensation are those in which two different molecules of ester or ester and other carbonyl compound are treated in presence of base. It often forms mixture of products. Synthetically useful products are obtained, when one of the component of reaction is non-enolizable. O O O Cross-Claisen condensation O NaOEt of benzaldehyde and H + OEt ethylacetate OEt

O O NaOEt, EtOH OEt + Cross-Claisen condensation OEt ,H3O of ethylbenzoate and ethylacetate O O

OEt

O O O O Cross-Claisen condensation NaOEt + of ethylbenzoate and Ph OEt Ph Ph Ph acetophenone O O O NaOEt, EtOH Cross-Claisen condensation + ,H3O of cyclohexanone and H OEt CHO ethylformate

H N COOMe O Cbz LDA, THF, H + -45 to -500C Honda, Y; Katayama, S; OtBu Ph Kojima, M; Suzuki, T; O O Izawa, K, Org. Lett., 2002, H N 4, 447 Cbz OtBu

Ph 97% Thioesters also undergo Claisen condensation.

O O MgBr2.OEt2 + tBu iPr2NEt, DCM,4h Claisen condensation of Bt SBn thioester gives O O

β-ketothioester tBu SBn 80% Zhou, G; Lim, D; Coltart, D.M, Org.Lett., 2008, 10, 3809 II. (E). Dieckmann Intramolecular Claisen condensation of diesters cyclisation in presence of a base is Dieckmann cyclisation. O O O OR 1. base

O 2. H OR

The mechanism for the OR Dieckmann cyclisation is O O analogous to that of the Claisen condensation. OR OR OR H Firstly one of the two O O esters is converted into an enolate ion. This enolate OR OR then attacks the second O OR O O O ester via nucleophilic acyl substitution resulting in a OR OR cyclic β-keto ester. Reaction can best be carried out for 1,6 and 1,7-diesters, which give five and six membered rings respectively.

COOEt COOEt 1. NaH, THF, EtOOC EtOH

2. H3O COOEt EtOOC O

O O O NaOEt COOEt EtO OEt More examples

EtOOC

MeOOC 1. tBuOK, tol O reflux 5 min 2. 18N H2SO4 THF, 4 h

N O N O 61% More examples

COOEt COOEt tBuONa, rt 10 min O Toda, F; Suzuki, T; Higa, solv. f ree S, J. Chem. Soc., 1998, 1, COOEt 3521 68% COSPh BzOCHN

tBuOK, THF Jackson, B.G; Gardner, J.P; N -780C Heath, P.C, Tet. Lett., 1990, O 31, 6317 MeOOC BzOCHN

N O OH COOMe 76% More examples COOMe

COOMe

N CN

tBuOK DeGraffenreid, M.R, et.al, THF, rt 0.5 h JOC, 2007, 72, 7455 OH

COOMe

N CN 87% Ho, J.Z; Mohareb, R.M; Ahn, J.H; Sim, NHPf T.B; Rapoport, H, COOMe LiTMP JOC, 2003, 68, 109 MeOOC THF -780C NHPf MeOOC O III. Michael addition Michael addition is nucleophilic addition of enolate to α, β-unsaturated carbonyl compound in presence of base.

H R H R base + EWG EWG EWG EWG

Michael reaction is conjugate addition of enolate to activated olefin and is thermodynamically controlled. There are two components of reaction, one is Michael donor, which is usually, 1,3-dicarbonyl compound, acetoacetic ester, active methylene compound, etc. The other component is, Michael acceptor which is usually, α, β-unsaturated carbonyl compound, α, β-unsaturated ester, etc. R R O

O O + O O base R R

R O R

H R R Mechanism : R R B -BH Base first, abstracts proton O O from donor and forms O O enolate. R R

O O O Enolate then attacks R R Michael acceptor and adds + to it, giving Michael O O R addition product. O O B H O O

R R R R

R O R O

O O Ph H N Pansare, S.V, Pandya, K, N H NO2 JACS, 2006, 128, 9624 DMF, rt + pTsOH NO2 Ph 86% (>99%ee) O [bmim]OH 3.5 h, rt + EtOOC COMe

Ranu, B.C; Banerjee, S, Org. Lett., 2005, 7, 3049 O

MeOC COOEt 90% NO2

+ MeOOC COOMe

N Okimo, T; Hoashi, Y; H H F3C N N Furukawa, T; Xu, X; S Takemoto, Y, JACS, 2005, CF 127, 119 3 toluene, rt, 9 h

MeOOC COOMe

NO2

89% (86% ee) Robinson annulation is Michael addition of IV. Robinson annulation methyl vinyl ketone to carbonyl compound followed by Aldol condensation to give annulene. O O NaOH +

O

Mechanism : H O Base abstracts proton from O OH ketone and forms enolate

O

H OH Enolate adds to Michael O acceptor via conjugate + O addition O O H O

OH O Michael addition product, O through intramolecular Aldol condensation, gives final product i.e. H α, β-unsaturated ketone OH O O OH

Reaction is useful in syntheses of six membered O NaOH ring in polycyclic + compounds O O Michael addition of enolate having second enolizable group, to an enone, is necessity for reaction to occur.

O O base +

O

O O TiOH, P4O10 DCM, 400C + O microwave, 8h

O Mc Murry, JOC, 1975, 40, 1. NaNH2 + 1823 2. NaOH, MeOH O O EtOOC

COOEt O 1. KOtBu Marshall, JOC, 1971, 36, + O 2. NaOMe/ 178 MeOH O

O NaOMe + MeOH COOEt reflux Wang, D; Crowe, W.E, 56% O Org. Lett., 2010, 12, 1232 EtOOC EtOOC H

H OH OH + HO H HO H H H H H

syn : anti 1 : 4 When diester is used as Michael donor, Claisen condensation, instead of Aldol condensation is seen. This reaction gives cyclic diketone.

COOEt O EtONa + EtOH reflux EtOOC COOEt O O

O EtONa EtOOC EtOH EtOOC Base catalyzed reaction between nitroalkane V. Henry reaction and carbonyl compound is Henry reaction.

NO2 O base 3 1 + R R NO2 R1 R2 R3 R2 OH

H Mechanism : O O B R1 N Mechanism is similar to R1 N aldol condensation. O O First base abstracts proton O O O B H from nitro compound and R1 N R1 + R3 2 gives enolate equivalent. It O R2 R3 R adds to carbonyl compound NO2 in similar way as that in OH Aldol reaction, to give R1 R3 β-nitro alcohol as product. R2 NO2 Reaction is analogous to aldol condensation and generally referred to as Nitro-Aldol reaction.

NO2 CHO OH CH3NO2, TMG THF, rt, 12h BnO OBn BnO OBn OBn OBn 58%

Nitro group, like, carbonyl moiety is powerful electron withdrawing group. It renders acidic properties to protons α to it and can form enolate equivalent. Acidic nature of nitro compounds is so profound that very mild bases can catalyze reaction. Like Aldol condensation, α,β-unsaturated nitro compound can be obtained, by elimination of

water molecule. O

Et3N, H2O 5h H + CH3NO2

OH

NO2 Zhou, C.L; Zhou, Y.Q; H Wang, Z.Y, Chinese Chem. Lett., 2003, 14, 355 88%

NO2 CHO HO OH

BnO O NO2 BnO TBAF/ THF O + rt, 10 h O O OH O O

75% is a chemical process in which a VI. Ester hydrolysis certain molecule is split into two parts by the addition of a molecule of water. One fragment of the parent molecule gains a hydrogen ion, other group collects the remaining hydroxyl group. Ester is hydrolyzed when treated with excess of water. This reaction is reverse of ester synthesis from corresponding and alcohol.

O O General reaction for ester acid / base + R'OH hydrolysis R OR' R OH Reaction is catalyzed by acid or base. Both yield same product, except that, in base catalyzed reaction of carboxylic acid is obtained from which acid can be regenerated by acidic work up. Acid catalyzed reaction is reversible. In order to get product in good yields, it is necessary to use dilute acid and ample amount of water, in contrast to that of ester synthesis, where concentrated acid is used. Ingold in 1940 classified these mechanisms according to following factors;  Nature of reagent  Point of cleavage  Reaction kinetics Mechanism of ester Ester hydrolysis can take place by eight possible hydrolysis mechanisms. Acid catalyzed, unimolecular, acyl oxygen AAC1 mechanism : fission O O O H O H H slow 2 R O R'OH R OR' R R' O OH O H R O R OH H R OH H

O* O*

H2SO4 Hydrolysis of methyl O OH+ CH3OH mesitoate H2O AAC2 mechanism : Acid catalyzed, bimolecular, acyl oxygen fission OR' O OH H H2O slow R OH2 R OR' R OR' OH OH OH O R' slow O R R'OH H OH R OH R OH H

AAL1 mechanism : Acid catalyzed, unimolecular, alkyl oxygen fission

O OH O H + R'

R OR' R OR' R OH

H H2O R'OH slow O R H H O OH H

Ph O Ph Ph O Ph

O H2 + Ph C OH Ph OH

AAL2 mechanism : Acid catalyzed, bimolecular, alkyl oxygen fission O O H R' H2O R O R OR' H O H + R'OH O R OH R' H H Base catalyzed, unimolecular, acyl oxygen B 1 mechanism : AC fission

O O slow OH + OR' R OR' R O O OR' + R'OH R OH R O

Base catalyzed, bimolecular, acyl oxygen BAC2 mechanism : fission OH O OH slow R OR' R OR' O O O + R'O + R'OH R OH R O O O

+ NH3 H3C C NH3

H3C OC2H5 OC2H5 O

+ C2H5OH

H3C NH2

BAL1 mechanism : Base catalyzed, unimolecular, alkyl oxygen fission

O O H2O slow + R' R OR' R O H OH R'OH O R' H BAL2 mechanism : Base catalyzed, bimolecular, alkyl oxygen fission

O O OH + R'OH R OR' R O

Though all these mechanisms are observed in many cases, AAL2 and BAC1 are not observed for any substrate.

Most common of all these mechanisms are AAC2 and BAC2 Evidence of acyl oxygen fission is obtained by following experiments. 18 18  Hydrolysis with H2 O, results in O appearing in acid and not alcohol  Esters with chiral R1 group, give alcohol with retention of configuration  Allylic R1 group, does not give  Neopentyl R1 group, does not give rearrangement All these observations indicate that O-R1 bond is not broken. Different nomenclature and summary of features of ester hydrolysis

Ingold notation Type Hydrolysis

AAC1 SN1 Special case

AAC2 Tetrahedral Very common

AAL1 SN1 Very common for tertiary alcohols

AAL2 SN2 -----

BAC1 SN1 -----

BAC2 Tetrahedral Very common

BAL1 SN1 Special case

BAL2 SN2 Rare Examples of ester hydrolysis

H H N N KOH, aq.DMSO COOEt COOH

1. 2mol KOH COOCH3 MeOH, COOH 25min, ~350C 2. 6N HCl

96%

O O 1. 3mol KOH MeOH, 0 O O 60min, ~35 C O OH 2. 6N HCl

O O 94% OH

OH O

OH O 1. 4mol KOH, MeOH, 60 min, OH ~350C 2. 6N HCl

OH OH

OH O 90%

Khurana, J.M; Chauhan, S; Bansal, G, Monatshefte fur Chiemie, 2004, 135, 83 PhSe PhSe O Me3TiOH O 1,2-DCE AllylO NHBoc 0 HO NHBoc N 80 C, 2 h N H H O O 100%

Wallner, S.R; Nestl, B; Faber, K, Tet., 2005, 61, 1517

NHBoc NHBoc 30mol% I , 5h OtBu 2 OH MeCN, reflux O O 89% MeO COOtBu MeO COOH

30mol% I2, 3h

MeO MeCN, reflux MeO

OMe OMe 82%

1. O.2N NaOH 30min, rt, DCM/ MeOH nC4H9 COOEt nC4H9 COOH 2. H3O The alkaline hydrolysis of esters to give carboxylate is known as saponification. Principal content of is or potassium salt of higher carboxylic acid i.e. a .

O C15H31

Alkaline hydrolysis OH O 0.2N NaOH of tripalmitin gives O DCM/ MeOH O ~2.5h, rt + OH and O C15H31 H3O C15H31 OH O O OH Palmitic acid + Glycerol

C15H31 Tripalmitin Practice problems Luche,J.L; Damiano,J.C; JACS, 1980, 102, 7926. (1) nBuBr Li, ether )))), 15 min CHO O HO nBu (3) THF, rt ~100% + MgCl (2) O OH MgBr OH H aq. NH4Cl

Tet. Lett., 2010, 66, 3242. (4) OH 92% O EtMgCl CeCl3 THF, 00C Et

76% JACS, 1989, 111, 4392.

(5) HO O PTSA O toluene HO O (6) Wada, S; Suzuki, H, Tet. Lett., 2003, 44, 399 calcite, 0.5h CHO + NC CN CN

H CN 97% S. Sebi, et.al, Tet. Lett., 2002, 43, 1813

(7) CHO Calcium phosphate CN NaNO3, MeOH, 15min + NC COOEt COOEt 81%

O (8) Al2O3 CN + 3 min H NC CN CN 88% Francoise, T.B; Foucaud, A, Tet. Lett., 1982, 23, 4927 (9) O NaOEt, EtOH +

O H OEt H

O H CHO (10) (11) KHMDS OBn OBn THF, 1h H H MeOOC N COOMe -780C MeOOC Bn OTBS NaHMDS O OTBS 0 N THF,-78 C N Bn N OH COOMe MeOOC 58% COOMe 90% Lin, R; Castells, J; Rapoport, H, JOC, 1998, 63, 4069