Klein-22

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Back 1

LAH will reduce Ester as far as possible (1. a. acyl substitution after Hydride attack => open up the ring / b. Hydride attack to open up the C=O / 2. protonation)

Front 2

Propose a way to perform the following transformation?

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1). Make grignard 2)attack of gringnard on CO2 to give carboxylic acid 3)Esterification

Front 3

Smell of many fruits are results by what type of compound?

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Esters

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Back 4

The molecule has two esteric bond which cleaves to give two alcholos and carboxylic acid with two OH on it which is unstable and decomposes to CO2

Front 5

Propose reagents to preform the following transformation?

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First the compound should be converted to an carboxylic acid and then to an amide (1-Byerviliger Oxidation -> insert O on the left side of C=O 2-acidic hydrolysis of Esters => carboxylic acids 3). Fromation of acid chlorides 4)Amonolysis of acid chlorides)

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Acetaminophen

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Benzene ring with hydroxyl and acetamide at para position

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describe different position in regard to distance with C=O group?

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Enolate

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Front 9

generally speaking in Keto-enol tautomerization, the position of equilibrium will significantly favor the ketone. In what circumstances the enol formation is favored? Example?

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1.The enol has a conjugated P system (2) the enol can form an intramolecular H-bonding interactions between the hydroxyl proton and the nearby carbonyl group (e.g. beta-diketones and Phenols)

Front 10

Why It is difficult to prevent tautomerization?

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Because keto-enol tautomerization can still be catalyzed by the trace amounts of acid or base that are adsorbed to the surface of the glassware

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Enolates are called ambient nucleophiles. Why?

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because they possess two nucleophilic sites, each of which can attack an electrophile (When the oxygen atom attacks an electrophile, it is called O-attack; and when the A carbon attacks an electrophile, it is called C-attack)

Front 12

Enolates can show two types of nucleophilic attack. What are they? Which one is more common?

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O-attack and C-attack . C-attack is more common (Although the oxygen atom of an enolate bears the majority of the negative charge)

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Presence of C=O in compound, makes hydrogen in …..position acidic.

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Alpha

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Aldehydes and ketones typically have pKa values in the range of …..

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Aldehydes and ketones typically have pKavalues in the range of 16–20

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Judge the quality of removal of alpha hydrogen of aldehydes or ketons by a.EtO- b.NaH c.LDA

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a. Equilibrium (but it does not favors enolate formation) / b.completely convert it to enolate / c.Equilibrium (but almost all of them are enlalte so equilibrium strongly favores formation of enolates)

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What is LDA? What is used for?

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Lithium diisopropylamide. Used to deporotonate alpha position of C=O

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With what kind of bases we can deprotonate the alpha position of beta-diketones?

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EtO- would be enough . LDA and NaH is not necessary (Since the H is in alpha position of two C=O is more acidic than usual alpha hydrogens)

Front 18

Define Alpha Halogenation of ketones (in Acidic condition)?

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Under acid-catalyzed conditions and existence of Cl2, Br2 or I2, the alpha position (of C=O) with more substitution undreroes halogenation(solvent could be acetic acid, water, chloroform, and diethyl ether)

Front 19

Define Alpha halogenation of ketones? (in basic condition)

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With bases like OH- , deprotonating at alpha position occurs then SN2 reaction

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What is the main problem of halognation in basic condition? Why this happens?

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Polyhalogenation because presence of the first halide makes the alpha position more acidic.

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Explain mechanism of alpha halognation of C=O (in acidic condition) ? Which one is the rate determining step?

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1.formation of enol (keto-enol tautormerizaiton) 2.Halogenation via nucleophilic attack (enol serves as a nucleophile to attack Br2). The rate determining step is the first one.

Front 22

Is the alpha halogenation of C=O group autocatalytic? Why?

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Yes. It produces HX which catalyzes the first step of the reaction

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What is the meaning of autocatalytic

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the reagent necessary to catalyze the reaction is produced by the reaction itself

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Which one the following products would be the major product of the alpha halogenation of the C=O group (1 or 2)? Why?

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1. Because the first step of the reaction goes via the more substituted enol (the more stable alkene)

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lithium carbonate? What is used for?

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Li2CO3. It is a moderate base to perform elimination of the halides at the alpha position of C=O

Front 26

What kind of bases can perform the following E2 reaction?

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Since the resulting alkene is conjugated even weak bases like tBuO- or pyridine can perform this reaction

Front 27

What is the strategy introducing alpha,beta-unsaturation in a ketone? (e.g the following example)

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1. Alpha halogenation (acidic condition) 2.Elimination

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What kind of compounds containing C=O group can not undergo alpha halogens (under acidic condition)? Why?

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Carboxylic acids, esters, or amides because these functional groups are not readily converted to their corresponding enols.

Front 29

Unlike ketones, Carboxylic acids can not undergo halogenation under acidic condition . How we can do alpha halogenation?

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By Hell-Volhard-Zelinski reaction which is a 2 step reaction as described below

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Define Hell-Volhard-Zelinski reaction?

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Halogenation of Carboxylic acids on alpha position by 1.Br2, PBr3 / 2. H2O [ Memorzie: vasate janhanam (hell) Ye bareye pokhte shode (Br) acid pashi mikone ru suratam (carboxylic acid) , vaghti dare suratam misuze par (PBr3) mikone tu chasham o bad shlinga ab ro mikone tu gusham (H2O) ]

Front 31

Explain mechanism of Hell-Volhard-Zelinski reaction?

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1.PBr3 gives acid halide 2.halogenation of C=O at alpha position 3.hydrolysis of acid halide to a carboxylic acid

Front 32

How a methyl ketone can be converted to the acetic acid?

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By haloform reaction: 1.excess base and excess halogen ( a. three alpha halogenation in basic condition / b.Nuchelophilic attack of OH- to kick trihalomethyl out) / 2.Protonation

Front 33

Define haloform reaction?

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Converting methyl ketones (when the other side of the ketone has no Alpha-protons.) to carboxyilic acids by 1.excess base and excess halogen ( a. three alpha halogenation in basic condition / b.Nuchelophilic attack of OH- to kick trihalomethyl out) / 2.Protonation

Front 34

In what condition halform reaction works the best?

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The haloform reaction is most efficient when the other side of the ketone has no Alpha-protons.

Front 35

Define Aldol addition?

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Addition of one aldehyde to itself via a nucleophile attack (to give a compound poses aldehyde and OH group at beta position)

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What is the mechanism of aldol addition reaction?

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1.deporotonation of alpha position to give enolate / 2. Nuclelophilic attack on C=O / 3. protonation

Front 37

Discuss the position of equilibrium in an aldol addition reaction for a. aldehydes b. ketones

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a. Equilibrium favors aldol product / b. Equilibrium disfavors aldol product

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What happnes to the Beta-hydroxy ketones in the presence of NaOH, H2O (basic condition)?

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retro-aldol reaction to give two ketones

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Despite the fact that aldol addition reaciton results in a poor yield for ketones, what would be the possible aldol product of the reaction? Why?

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Carbonanion intermediate forms at the less substituted position

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Define aldol condensation?

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A two-step process (aldol addition plus dehydration) of an aldehye or ketone is called an aldol condensation. The final product is and alpha,beta-unsaturated compound

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What condensation means? (e.g in aldol condesation)

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any reaction in which two molecules undergo addition accompanied by the loss of a small molecule such as water, carbon dioxide, or nitrogen gas

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In Aldol condesation, what kind of dehydration happens (E1, E2)?

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Neither. It is called E1cb mechanism which unlike the other ones, the leaving group only leaves after deprotonation occurs

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Predict the major product of aldol condensation?

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In aldol condensation cases where two stereoisomeric P-bonds can be formed, the product with the least steric hindrance is generally the major product.

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At low temperature = aldol addition / at higher temperature aldol condensation (notice: the yield of the top reaction is very poor. As explained earlier, the starting material is a ketone, and the equilibrium does not favor formation of the aldol addition product )

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How we can easily draw the product of aldol condensation of the following compound?

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(1.Draw two molecules of ketones wehre O of C=O and two alpha Hydrogens are colse 2. remove the water molecule tconnect the carbons with a double bond as follows:

Front 46

What is crossed aldol (mixed aldol) reaction?

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Aldol reaction with between two different aldehyde or ketone (wich result in a mixture of product of the possibility of aldol reaction between each compound with itself and the other compound

Front 47

What would be the product of aldol condensation of the following compound?

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In what condition crossed aldol condensation would be practically useful?

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1.when one of the starting material is formaldehyde and benzaldehyde which do not undergo self-aldol reaction / 2. directed aldol addition: Use LDA on of the starting materail to convert it to its enolate ion then mix it with second C=O containing comound

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Intramolecular Aldol condensation

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Define Claisen Condensation?

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Reaction of an ester with itself in a basic condition via deprotonating and nucleophile attack of alpha position

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Discuss mecahnism of the Claisen condensation?

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1. (a. deprotonation of alpha carbon / b. Acyl nucelphilic substitution) 2. protonation

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can Hydroxide be used as the base for a Claisen condensation? Why?

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No. because it can cause hydrolysis of the starting ester

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What kind of base is usually used for Claisen condensation? Why?

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RO- same as OR of the ester (because OH- cause hydrolysis of the ester and other OR- can force transesterification

Front 54

In what condition crossed Claisen condensation is practically useful?

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(1. one of esters has no alpha hydrogen) or (2.Using a base like LDA to deprotonate alpha hydrogen of one the esters prior to mixing with the other one)

Front 55

Define Dieckmann cyclization?

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It is just a Intramolecular Claisen Condensations [Memorize: Dick gir karde tu Closet e khune)

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How to perform Alkylation of alpha position (of ketones) ?

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1)strong base like LDA to convert ketone completely to enolate ion (OH- and OR- cannot be used) 2) a simple SN2 reaction with an alkyl halides

Front 57

Define thermodynamic enolate and Kinetic enolate?

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When forming enolates, The more-substituted enolate is more stable and is called the thermodynamic enolate . The less-substituted enolate is less stable, but it is formed more rapidly and is therefore called the

Front 58

Write condition to perform the two following reactions?

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1.Alkylation via Kinetic enolate : low temperature and LDA // 2. Alkylation via thermodynamic enolate: Room temperature and a nonsterically hindered base (such as NaH)

Front 59

Define malonic ester synthesis?

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To synthesize carboxylic acid bearing an alkyl substitution on alpha poistion by 1)deprotonation of malonic ester at alpha position 2)SN2 attack on RX 3)Acidic hydrolysis to give a dicarboxylic acid compound 4)decarboxylation by heat to give monosubstituted acetic acid

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Malonic ester

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Front 61

Explain mechanism of decarboxylation?

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1. [1,5] Pericyclic reaction 2.keto-enol tautomerization

Front 62

Synthesize the following compound by malonic ester synthesis?

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Two successive malonic ester synthesis

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Synthesize by malonic ester synthesis?

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Front 64

Define acetoacetic ester synthesis?

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Synthesize ketones with substitution at alpha poistion (very similar to malonic ester synthesis) : 1)deprotonation of acetoacetic ester at alpha position 2)SN2 attack on RX 3)Acidic hydrolysis to give a compound with two C=O at one carbon 4)decarboxylation by heat to give monosubstituted acetic acid 5)keto-enol tautomerization

Front 65

acetoacetic ester ?

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Front 66

Synthesize the following compound by acetoacetic ester synthesis?

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Front 67

Define michael donor and acceptor?

Back 67

the doubly stabilized enolate is called a Michael donor, while the Alpha,Beta-unsaturated aldehyde is called a Michael acceptor

Front 68

Define michael reaction?

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A 1,4-conjugate addition of a Micheal donor to the beta position of a Micheal acceptor to give a 1,4-conjugate addition (which after keto-enol tautomerization seems like a 1,2-addition)

Front 69

There are two electrophiles in an alpha,beta-unsaturated compoud. Explain what kind of carbon nucleophile attacks which one of these elecctophilic sites? (a. Grignard reagent RMgX / b.Gilman reagent R2CuLi)

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a. Attacks C=O b. attacks double bond to gaive 1,4-addition (which after keto-enol tautomerization seems like a 1,2 addition)

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Michael reaction does not occur because michael donor should be doubly stabilized enolates

Front 71

Define Stork enamine synthesis? What is used for?

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To perform a michael reaction on a simple ketone by (1) formation of an enamine, (2) a Michael addition, and (3) hydrolysis.

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What is Robinson annulation reaction?

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A two step process to make a ring by 1). Michael addition 2) aldol condensation

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How to do Alkylation of the Alpha and Beta Positions for ketones?

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1). Michael addition (=> beta substution) 2). Treatment with RX (SN2 reaction)

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1). Michael addition (=>1,4-conjugate addition and formation of enolate) 2). SN2