Organic Chemistry 2 Chapter 21

alpha carbon in relation to carbonyl group

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beta carbon in relation to carbonyl group

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alpha protons

protons attached to an alpha carbon

enol intermediate

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enolate intermediate

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tautomers

Isomers that can interconvert by changing the location of a proton

in the presence of _____ a ketone or aldehyde exists in equilibrium with an enol

catalytic acid or base

are a ketone or enol generally favored at equilibrium?

ketone is generally favored

what is unique about 1-3-diketone?

the enol of 1,3-diketone is stabilized by conjugation and intramolecular H-bonding; it is more stable than a typical enol and is favored at equilibrium.

the alpha position in an enol is ______.

nucleophilic through resonance.

why is an enolate much more nucleophilic than an enol?

it carries an overall negative charge

an enolate can undergo what type of attack?

C-attack or O-attackbut it generally undergoes a C-attack

C-Attack

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O-Attack

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Two possible enolate C-attacks

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________ are the only acidic protons on an aldehyde or ketone that can be removed to form an enolate.

Alpha protons

are beta or gamma protons acidic?

no

will deprotonation of beta or gamma protons yield a resonance stabilized intermediate?

no

how to make an enolate

through the deprotonation of a molecule's alpha carbon

what happens when the pKa values of the base and enolate are similar?

both products and reactants are present in significant amounts

LDA

a strong base commonly used to form enolates irreversibly

LDA full name

lithium diisopropylamide

LDA structure

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how to make LDA?

treating diisopropylamine with n-butyllithium

when LDA is used to form an enolate, the amount of ketone present at equilibrium is _____.

negligible

LDA features

two bulky isopropyl groups, which allows it to be a strong base, but not a good nucleophile

what happens to an alpha proton's acidity if it is alpha to two carbonyl groups?

they are much more acidic

why are protons that are alpha to two carbonyl groups much more acidic?

the increased stability of the resulting enolate

do you ever use NaH or LDA to form the enolate of 1,3-dicarbonyl?

no. they are already acidic enough to be irreversibly deprotonated by an alkoxide so using these would be overkill.

1,3-dicarbonyl

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what base do you use if you want to form an enolate from a ketone and have both the enolate and ketone present at equilibrium (reversible)?

NaOH or NaOEt

what base do you use if you want to form an enolate from a ketone and have irreversible enolate formation?

NaH or LDA

what base do you use if you want to form an enolate from a 1,3-dicarbonyl compound?

NaOH or NaOEt. Adding LDA would be unnecessary because this is already irreversible

under _____ conditions, ketones/ aldehydes undergo alpha halogenation.

acidic

what halogens can be added via alpha halogenation to a ketone or aldehyde?

Cl2, Br2, I2 (not fluorine)

acidic conditions means an _____ is the reactive intermediate

enol

with alpha halogenation, where does the halogenation occur if the ketone is unsymmetrical?

-halogenation occurs after at the more substituted carbon-the major product results from the more stable (more substituted) enol

Alpha halogenation provides a two-step synthesis for the synthesis of

alpha,beta-unsaturated ketone

alpha, beta-unsaturated ketone

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bases that can be used to make an alpha, beta-unsaturated ketone via an alpha halogenation

1.pyridine2.t-BuOK3.Li2CO3

Hell-Volhard Zelinski (HVZ) reaction

brominates the alpha carbon of a carboxylic aciduses 1)Br2, PBr3 2)H2O

can alpha halogenation be achieved also under basic conditions?

yes

under basic conditions, _____ is the reactive intermediate

enolate

when doing alpha halogenation under basic conditions, what can often happen?

poly-halogenation (multiple Br's adding)

haloform reaction

under basic conditions, methyl ketones are converted to carboxylic acids using excess halogen and hydroxide1) NaOH, Br2------------->2) H3O+

bromoform

CHBr3

what halogens can be used in a haloform reaction?

Br2, Cl2, I2

what are the best conditions for a haloform reaction?

it works best if the other alpha carbon has no alpha protons (there is a tertbutyl or something as one of the carbon groups)

aldol addition reaction

when an enolate attacks the aldehyde

is aldol addition an equilibrium process?

yes

for simple aldehydes undergoing an aldol addition reaction, what part of equilibrium is favored?

aldol product

for most ketones undergoing an aldol addition reaction, what part of equilibrium is favored? why?

the ketonethe intermediate of this reaction has steric hinderance, therefore making the forward reaction unfavored.

what are some features of the product of aldol addition?

-there will be a hydroxyl (OH) in the beta position-there will be an alcohol and carbonyl group

retro-aldol reaction

The reverse of an aldol condensation reaction, in which a carbon-carbon bond is cleaved with heat and base, yielding two aldehydes, two ketones, or one of each.

when an aldol product is heated under acidic or basic conditions, what forms?

alpha, beta-unsaturated carbonyl(a double bond between the alpha and beta position with loss of OH group in beta position)

aldol condensation

when an aldol product is heated under acidic or basic conditions, yielding a new double bond between the alpha and beta positions

what is the difference between aldol condensation and aldol addition?

aldol addition is simply adding two molecules together due to an enolate attack while aldol condensation drives that process further via heat and an acid or base condition to yield a new double bond between the alpha and beta carbons with the OH on the beta carbon leaving.

what is more favored, Aldol addition or aldol condensation?

aldol condensation, it is often impossible to isolate the aldol addition product

what usually has greater product yield? aldol condensation or aldol addition?

aldol condensation has much greater yield rather than the initial ketone/aldehyde being favored. This is due to the product having much more stability through conjugation

when performing an aldol reaction/condensation under acidic conditions, what product is usually yielded?

condensation product

two different aldehydes in crossed aldol reaction yield how many possible products?

4 possible aldol products

mixed aldol reaction

two different aldehydes/ketones react in a crossed aldol reaction (or a mixed) aldol reaction

how can a crossed Aldol reaction be practical?

if the number of products can be minimized

how can you minimize the amount of product through a crossed aldol reaction?

1. if one of the substrates is relatively unhindered and without alpha protons2. LDA is used as a base

direct aldol addition

-using LDA as a strong base in a crossed aldol reaction in order to minimize the amount of product.-this works because one compound is completely converted to enolate with LDA and the other carbonyl compound is then slowly added to the enolate

intramolecular aldol reaction product

-cyclic compounds-only 5 and 6 membered rings can form well in this way-this happens through one of the groups forming an enolate and attacks the other group

Claisen condensation

esters undergo reversible condensation reactions-nucleophile= enolate of an ester-electrophile= ester

what type of reaction is a claisen condensation reaction?

nucleophilic aryl substitution reaction

what is the preferred enolate that you should draw on an exam?

have the negative on the O because this is the major product

what are the three limitations to clause condensation?

1. the starting ester has to have 2 alpha protons because the removal of the second proton by the alkoxide ion is what drives the equilibrium forward2. hydroxide (-OH) cannot be used as a base to promote Claisen condensation; otherwise ester hydrolysis occurs.3. an alkoxide that matches the -OR group of the ester is needed or else mixture of esters occurs (transesterification).

transesterification

mixture of esters

crossed claisen condensations are only useful if one of the following criteria is met:

1. one ester has no alpha protons2. perform directed Claisen condensation with LDA as the base

Dieckmann cyclization

intramolecular claisen condensations

what type of rings can form through Dieckmann cyclization?

5 or 6 membered rings

what type of reaction is the alkylation of the alpha position?

the enolate attacks the alkyl halide via an SN2 reaction

alkylation of the alpha position limitations

-1' alkyl halides are favored. if a 2' of a 3' alkyl halide is used, E2 elimination predominates-the aldol reaction also completes with the desired alkylation, so a strong base like LDA must be used-regioselectivity is an issue with unsymmetrical ketones (two different enolates can form)

kinetic enolate of alkylation of the alpha position

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thermodynamic enolate of alkylation of the alpha position

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the kinetic enolate is favored by _____ conditions so you use ____ at ____ temperature(s).

irreversibleLDAlow

the thermodynamic enolate is favored by _____ conditions so you use ____ at ____ temperature(s).

reversibleNaHroom

masonic ester synthesis

alkyl halide is converted into a carboxylic acid with 2 additional carbons-starting material diethyl malonate reacts with a base to make the corresponding enolate which then reacts with the alkyl halide

diethyl malonate

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1,3-dicarboxylic acids undergo decarboxylation in a ____ process.

pericyclic

decarboxylation

The complete loss of a carboxyl group as carbon dioxide

aldol condensation products (a,B-unsaturated carbonyls) have how many resonance structures?

3

aldol condensation products (a,B-unsaturated carbonyls) what carbon can be attacked?

either the carbonyl one or the one on the double bond farther from the carbonyl depending on the nucleophile used

gilman reagents

R2CuLi

Grignard reagents generally attack the ______ position of a,B-unsaturated carbonylsthis is called _____ addition

carbonyl1,2 addition

Gilman reagents generally attack the ______ position of a,B-unsaturated carbonylsthis is called _____ addition

beta1,4 addition or conjugate addition

tautomerization

The rearrangement of bonds within a compound, usually by moving a hydrogen and forming a double bond

conjugate addition

Addition of a nucleophile to the beta carbon of an alpha, beta unsaturated carbonyl compound.

stronger nucleophiles tend towards ____ addition; less reactive nucleophiles tend to ____ addition

1,2conjugate

stabilized enolates give ___ addition exclusively

1,4

Michael reaction

conjugate (1,4) addition

Michael donor

nucleophile that does conjugate addition

Michael acceptor

the a,B-unsaturated carbonyl

Michael donors that give exclusively 1,4-addition with an unsaturated carbonyl compound

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Common Michael acceptors

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how do enamines behave like enolate?

they are nucleophiles through resonance so they behave like enolate ions

enamine characteristics (nucleophilic, Michael)

it is less nucleophilic than an enolate ion and is a Michael donor

Stork Enamine Synthesis

(1) formation of an enamine, (2) a Michael addition, and (3) hydrolysis

stork enamine synthesis product

1,5-dicarbonyl compounds

aldol and claisen product

1,3-difunctional compounds

what type of enolate does LDA form?

it will make the double bond on the less substituted carbon