Acetoacetic Ester Synthesis

Home , Diethyl malonate, Ethyl acetoacetate

Programme: B.Sc. B.ed. (Integrated) Course: ORGANIC CHEMISTRY- III Semester: VI Code: CHE-352

Topic: ETHYLACETOACETATEE Date- 07/04/2020 y Only

PPe Dr. Angad Kumar Singh ForF Department of Chemistry, Central University of South Bihar, Gaya (Bihar)

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia.

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Ethylacetoacetate

The Claisen Condensation between esters containing - hdhydrogens, promotdted byabase such as sodium ethoxy ide, toproduce a - ketoester. One equiv serves as the nucleophilele (enolate)(eno and the other is OnlyO the electrophile which undergoes additiontion andae elimination. The use of stronger bases, e.g. sodium amide or sodiumsodUse hydride instead of sodium ethoxide, often increases the yield.d. al onal

Ethylacetoacetate

Like mixed aldol reactions, mixed Claisen condensations are useful if differences in reactivity exist betweenn they two esters as for example when one of the esters has no -hydrogenydrogOnlyO . Examples of such esters are: e Use

ers

excess

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Diethyl malonate

Diethyl malonate may be prepared by reacting the sodium salt of chloroacetic acid with sodium cyanide, followedowedy by base hydrolysis of the resultant nitrile to give the sodiummOnlyO saltsal malonicacid. Fischer esterification gives diethyl malonate . e Use l nal

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Acidity of alpha-Hydrogens Alklkyl hdhydrogen atoms bddbonded toacarbon atom in a (lh)(alpha) position relative to a carbonyl group display unusual acidity.The

pKa values for alkyl C-H bonds is typically ony thet order of 40-50, pK values for these ()alpha hydrogens is the ordero of 19-20. This can a OnlyO most easily be explained by resonancenancee stabilizations of the product carbanion, as illustrated in the diagramagramUse below. al

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. In the presence of a proton source, the product can either revert back into the starting ketone or aldehyde or can form a new product, the enol. The equilibrium reaction betweenbetww the ketone or aldehyde and the enol form is commonly referredreferr to as "keto-enol OnlyO tautomerism". The ketone or alde hy de issgen generae lly strongly fdfavored in this reaction. Use Because carbonyl groupsups arearal sp2 hybridized the carbon and oxygen both have unhybridizedized p orbitals which can overlap to form the C=O bond. Personal

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. The presence of these overlapping p orbitals gives hydrogens (Hydrogens on carbons adjacent to carbonyls) special ppproperties. In pp,articular, hyygdrogens are weaklea y acidic because the conjugate base, called an enolate, is stabilizedbilizedy thoughth conjugation with the orbitals of the carbonyl. The effectffeectOnlyOof the carbonyl is seen when comparing the pK for the hydrogenshydrog of aldehydes (~16-18), a Use ketones (~19-21), and esters (~23-25) tot the pK of an alkane (~50). al a Of the two resonanceceonal strstructures of the enolate ion the one whic h pllaces thenegative cPersoPehargea on the oxygen is themost stbltable. This is because the negativegative cchange will be better stabilized by the greater electronegativity ofth theForF oxygen.

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Programme: B.Sc. B.ed. (Integrated) Course: ORGANIC CHEMISTRY- III Semester: VI Code: CHE-352

Topic: KETO-ENOLTAUTOMERISMO Date- 09/04/2020 y Only

PPe Dr. Angad Kumar Singh ForF Department of Chemistry, Central University of South Bihar, Gaya (Bihar)

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia.

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Keto-enol TiTautomerism The acidity of hydrogens carbonyls undergo keto-enol tautomerism. Tautomers are rapidly interconvertedonvery constitutional isomers, usually distinguished by a differententOnlyO bondingbo location for a labile hydrogen atom and a differentlyentlye locatedl double bond. The equilibrium between tautomers is notUse only rapid under normal conditions, but it often stronglyy favorsfaval one of the isomers (acetone, for example, is 99.999% keto tautomer). Even in such one-sided equilibria, evidence foror thehePersonalPe presence of the minor tautomer comes from the chemical behaviorehavioForF of the compound. Tautomeric equilibria are catalyzed by traces of acids or bases that are generally present in most chemical samples.

2) Enol formation Pe r

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. How Enols React

U al Alkylation of diethyl malonateate is knownk as Malonic Ester Synthesis Malonic ester issarea a reagent sppfecificall yused in a reaction which converts alkyl halidesdes toPersonalPe carboxylic acids called the Malonic Ester Synthesis. Malonicic esteresForF synthesis is a synthetic procedure used to convert a compound into a carboxylic acid

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Sodium Malonic Ester Due to the fact that Malonicnic ester’sesteUsUse hydrogens are adjacent to al two carbonyls, they can be deprotonatedprotonnal by sodium ethoxide (NaOEt) to form Sodium Malonic Ester.r. Person

Sodium Malonic Ester is an enolate, it can then be alkylated with alkyl halides.

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. After alkylation the product can be converted to a dicarboxylic acid through saponification and subsequently one of the carboxylic acids can be removed through a decarboxylation step y Only

Mechanism PersonalPe Step-1 Saponificationion For

OnO Step-3 TtTautomeri itization e Use

Alkylation of ethyl acetoacetateacetatPersPe is known as Acetoacetic Ester Synthesis The acetoaceticacetic eester synthesis allows for the conversion of ethyl acetoacetate into a methylForFt ketone with one or two alkyl groups on the alpha carbon

Step-2 Alkylation via andnd SNPerPe2 Reaction For

Addition of a second alky group After the first step and additional alkylalkylk OnlyOgroup can be added prior to the decarboxylation step. Overall this allowsllowsUse for the addition of two different alkyl groups. al

Topic: ALKYLATION Date- 11/04/2020 y Only

PPe Dr. Angad Kumar Singh ForF Department of Chemistry, Central University of South Bihar, Gaya (Bihar)

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia.

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Direct Alkylation Both the malonic ester synthesis and acetoacetic ester synthesis can be preformed with relatively mild bases, suchuchhyas sodium ethoxide, because of the unusually acidic nature ofthe dicdicarbonyl compounds. OnlyO However, if astronger basee eisused,such as LDA, monocarbonyl compounds can alsob bee alkalkylatedUse in the alpha position. al

Mechanism P Step-1 Enolate formationormatio ForF

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Step-2 SN2 attack

O 1, 3-dithiane (Umpolung Reagent ) e The dithiane can be madeb byyth theUse reaction of an aldehyde with 1,3-propane dithiol with lewis acidcidnal catalyst.caal The hydrogen on the cabon attached to two sulphur atomsms can be removed by reaction with base. After the reaction the 1, 3-dithianedithiaPersonPe system can be reconverted to corbonyl compound by acidhydro hydrolysisForF in the presence of Hg(II) ion. The 1, 3-dithiane anion can be alkylated by a variety of reagents like primary, secondary, haloalkanes, aldehydes, ketone and epoxides.

S S S S + I H H Li r BuLi BuLi ere CH2(CH2)2Cl PePersonalP Cl S H H S S S r Hg2+ ForF H2O

Enamines act as nucleophilescleoph in a fashion similar to enolates. Because of this enamines can beb used as synthetic equivalents as enolates in PersonPe many reactions. This processproce requires a three steps: 1. Formation of the enamineenanaForF , 2. Reaction with an eletrophile to form an iminium salt, 3. Hydrolysis of the iminium salt to reform the aldehyde or ketone.

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia. Some of the advantages of using an enamine over and enolate are enamines are neutral, easier to ppprepare ,and usualla y prevent the over reaction problems plagued by enolates. Thesese reactionsreacty are generally known as the Stork enamine reaction OnlyO e Use

y nly

Alkylation of an Enamine Use EiEnamine undergo an SN2 reacaltit on with reactive alkyl halid es to give the iminium salt. The iminiumiumonal saltsa can be hydrolyzed back into the carbonyl. Step 1: Formation of an enaminenamPersoPe ForF

Step 3: Reform the carbonyl by hydrolysis U al

All three steps together: theheFor

1) Formation of the enamine y nly

2) Nucleophilic attack erso

4) Reform the carbonyl by hydrolysis Us l

P ForF All three steps together:

Note: These materials are only for classroom teaching purpose at Central University of South Bihar. All the data taken from several books, research articles including Wikipedia.