Thẻ ghi nhớ: UBC Chem 213 Chapter 19 | Quizlet

Aldehyde + Aldehyde

Aldol condensation, in polar solvents and acid/base catalysts.

Aldol as an intermediate, enone/enal as a product. With 2 different aldehydes, 4 products are formed.

Aldol

OH on beta-carbon.

How does base catalysis of aldol condensation work?

Base deprotonates the aldol donor, producing enolate. The enolate attacks the aldol acceptor, OH leaves recreating the catalyst.

Conditions for retro-aldol reaction

Water, at pH~11-13. The reverse of aldol reaction.

How does acid catalyzed aldol condensation work?

Enol is formed and attacks the activated (protonated) aldehyde molecule. Acid is then recreated.

Generally, acid-catalyzed aldol condensation is useful for intramolecular reactions.

Hydrolysis is effective.

Define crossed aldol reaction, give the conditions.

Aldol reaction with two different carbonyl compounds that gives a single, well defined product.

Conditions: one of the aldehydes has no alpha-protons (and cannot enolize) and cannot self-condensate to a significant extent.

One of the enolates may have a subtantially lower pKa (Knoevenagel reaction)

Knoevenagel aldol condensation

Aldol condensation with a low-pKa enolate and tertiary amine as a weak base.

Triethylamine picks up the proton from a low-pKa enolate which results in a resonance-stabilized anion. The double bond of the anion then attacks the acceptor (carbonyl carbon), forming a sp3 product. Triethylamine will pick up a proton from an aldol, C=C will be made and OH- will coordinate with triethylamine ion.

What are some examples of low-pKa donors for Knoevenagel reaction?

Diethyl malonate (pKa ~13), Ethyl acetoacetate (pKa~11), dimethyl malonate (pKa ~10), benzyl methyl malonate (pKa ~9.5), malononitrile (pKa ~9), ethyl cyanoacetate (pKa ~10), nitroalkane (pKa~8)

Intramolecular aldol condensation

Ketone always attacks aldehyde. 5/6 membered ring is formed. Clean reactions happen with aldehyde and ketone with clear regioselectivity.

Dirty reactions happen with two ketones with no clear regioselectivity.

Describe the basics of Claisen reaction

Two esters react to give a beta-keto ester. The ester undergoes enolization to produce small amount of ester enolate which act as a nucleophile in the nucleophilic acyl substitution with the non-enolized ester.

The base used corresponds to the ester used. OH- can't be used not to cleave the ester.

Beta dicarbonyl compound is produced.

Claisen reaction for two esters that are the same

Ester in alcohol as a solvent = beta-dicarbonyl

Claisen reaction for two different esters

A mess of products

What kinds of esters cannot self-react in Claisen condensation?

The esters with one or no alpha protons cannot undergo self-condensation.

What acceptors are used in crossed Claisen condensation reactions?

Esters with one or no alpha protons (formate esters included).

What are the conditions for crossed Claisen reaction?

Acceptor is used in large excess to prevent self-condensation of a donor.

Dieckmann Condensation reactions

Intramolecular Claisen condensation reactions.

Michael Reaction

1,4 conjugate addition reaction

What reagents does Michael addition work with?

Amines, thiols, CN, alkoxides, enolates of ethylacetoacetate and diethylmalonate, enamines and organocuprates.

Can Grignard reagents and organolithiums perform Michael addition?

No - will undergo 1,2 addition.

How are enamines formed?

From aldehyde or ketone with secondary (typically cyclic) amine.

When ketone is used, less substituted enamine is favoured due to sterics. Trans double bond is favoured if possible.

What is the reactivity of enamines?

Enamines practically react like enolates in:

1) Alkylation with activated halides (i.e. bromoketone, allylbromide etc)

2) Most michael acceptors

3) Aldol-type reactions with aldehydes

4) Claisen-type reaction (only with acid halides)

List 4 useful amines

Piperidine, morpholine, pyrrolidine, proline

How does Robinson annulation work?

1) Michael addition

2) Aldol condensation

in tBuOK, usually a 6-membered ring is formed.

Enone + enolate (generated with the addition of a base) -> enone

How to synthesize diethylmalonate (DEM)?

Acetic acid + Br2/H+ -> bromoacetic acid + KCN/K2CO3 -> cyanoacetic acid + KOH/H2O -> malonic acid ion + EtOH/H2SO4 -> diethylmalonate. (pKa~13)

How to synthesize ethyl acetoacetate (EtAA)?

2x ethyl ethanoate + EtO- (Cat.) then acid work-up -> ethyl acetoacetate.

Claisen condensation.

What is the benefit of low-pKa enolates?

They allow using EtO- or carbonate as a base. Once the enolate is alkylated, the electrophile can attack the ester (sapponification) and the free carboxylic acid can be decarboxylated into CO2.

How are enolates formed directly?

Through direct aldol/Claisen condensation. A strong base, s.a. LDA, NaH is added to create the enolate.

How many enolates are formed through direct Claisen/Aldol condensation for asymmetric ketones?

Two: a thermodynamic and kinetic enolate.

Reactivity and other notes on dinitriles/dicarbonyl compounds.

1) Referred to as "stabilized enolates".

2) pKa~9-13 (depends on the side groups).

3) Readily deprotonated by KOH, MeO-, sometimes by carbonate and triethylamine (TEA).

4) no need of a strong base when reacting those, really.

Reactivity and other notes on aldehydes.

1) pKa ~17-19, electron withdrawing groups (e.g. F, Cl etc.) would lower the pKa to 13-16, electron-donating groups (R2N) would raise the pKa (19-20).

2) Usually readily alkylated by tBuOK, but LDA and NaH are often used.

Reactivity and other notes on ketones.

1) pKa ~19-24 depending on inductive groups, EWGs can lower the pKa and EDGs can raise it.

2) tBuOK might work with deprotonating, but usually NaH and LDA are used.

Reactivity and other notes on esters.

1) pKa ~23-25 depending on inductive groups.

2) Not readily deprotonated by tBuOK, with some exceptions.

3) Alkoxides are useful in Claisen/Diecmann reactions

4) NaH/LDA are used.

Reactivity and other notes on amides.

1) pKa ~26-28 depending on inductive groups.

2) Only LDA/NaH can deprotonate the groups well enough.

3) Not useful with secondary or primary amides because the proton on the amine has lower pKa and thus tends to have a more rapid acid-base chemistry going on.

Aldehyde/ketone/ester/amide + LDA

Enolate

Enolate + primary halide/tosylate

Alkylation reaction.

Double bond attacks the halide and forms a ketone/aldehyde.

Enolate + Enone

Michael addition, dicarbonyl formed.

Enolate + Aldehyde

Aldol condensation -> dehydrated aldol product is formed.

Enolate + Ester

Claisen Condensation, beta-carboxylate is formed.

Zaitseff rule for LDA reaction with asymmetric ketones

More substituted enolate is preferred. Thermodynamic enolate. More stable.

Is made by direct addition of 0.97 eq. of LDA.

LDA is slowly added to ketone.

Hoffman rule for LDA reaction with asymmetric ketones

Less substituted enolate is preferred.

Kinetic enolate. Less stable, but forms faster.

Is made by inverse addition of 1.2 eq. of LDA.

Inverse addition means that ketone is slowly added to LDA.

Reformatsky reaction

Enolate out of a bromo-ester (use Zn like Li in organolithium reagents).

What are the common mistakes with enolate alkylation problems?

1) The base has to be strong enough to form an enolate from carbonyl compound. If it is not strong enough, the reaction won't proceed. Elimination (E2) or SN2 of the base with the electrophile may be competing reactions in these cases.

2) The enolate is non-stabilized and hence will give elimination instead of substitution.