Organic Chemistry Chapter 21: Alpha Carbon Chemistry

What is an alpha carbon?

A carbon atom of focus, typically something that has groups attached to it.

What is a carbonyl carbon?

A carbon atom double bonded to an oxygen atom

How do you refer to carbons next to the alpha carbon/Carbonyl Carbon?

more greek letter (Beta then Gamma then Delta...)

Does a carbonyl carbon ever get referred to as as the alpha carbon?

No

When there is a carbonyl carbon, which carbon atom in a chain is the alpha carbon?

The carbons adjacent to the carbonyl carbon.

Can alpha carbon hydrogens be deprotonated easily?

Yes, if they're next to a carbonyl.

What is the difference in pKa between a ketone and a alkane?

like 50 or so

What is an enolate?

Deprotonated alpha carbon; nucleophile

What is an enol?

a compound with a double bond and an alcohol group

How do you make enolates from ketones?

deprotonation of the alpha carbon

How do you make Enols from ketones?

Tautamerization

When acetone undergoes taurtermerization, is the ketone or enol preferred?

Ketone form

When it comes to determining what side of equilibrium is preferred, what are some things to look out for?

Sterics (Less Sterics, more reactivity)
Intermolecular Forces (Hydrogen Bonds, specifically)
Conjugation (Resonance)
Aromaticity

Why are alpha carbons so reactive?

Second-Best Resonance Form Rule

What does it mean when something is ambident?

It can either nuc. attack with the oxygen or the alpha carbon.

Enolates are:

Ambident

When the oxygen atom in an enolate nuc. attacks, it's referred to as:

O-Attack

When the alpha carbon in an enolate nuc. attacks, it's referred to as:

C-Attack

What is a Silyl Enol Ether?

A protected oxygen atom.

What is typically the pKa of an alpha carbon adjacent to a ketone/aldehyde?

16-20

When it comes to picking a base to create an enolate, what should you consider when it comes to pKa?

Bases that create conjugate acids with pKas similar to the ketone/aldehyde will cause equilibrium to create a relatively decent amount of the enolate.

Bases with conjugate acids that have pKas MUCH higher then the ketone/aldehyde will cause equilibrium to create a ton of enolate.

What are the best bases to use when it comes to create an enolate?

NaH and LDA (Lithium Di-isopropyl Amide)

Is LDA actually an amide?

No.

How can you easily prepare LDA?

Deprotonate diisopropylamine with something like BuLi*THF.

Is LDA a strong base/Strong Nucleophile?

It is a strong base but not a very good nucleophile.

Why is LDA not a good nucleophile?

It's bulky/Sterically hindered

Is LDA soluble in organic or inorganic solvents?

Organic

Is the boiling point of LDA high or low?

Low

What is the pka of a dione?

Around 9 or so

Why are diones more acidic then mono-ones?

Resonance of the alpha hydrogen that's between both diones.

Is it a good idea to use LDA on a dione?

No, because it's WAY too basic.

What reagents are used for Autocatalytic Halogenation?

Br2 and H2O

What are the byproducts of Autocatalytic Halogenation?

HBr and Hydronium

What is Autocatalytic Halogenation?

The addition of a halogen atom to an alpha carbon

Why does Autocatalytic Halogenation work?

It promotes the creation of a halohydrin since there is an alkene present at some point

Why is autocatalytic Halogenation called what it is?

Because it gets faster and faster due to more disruption caused by Le' Chatlier's Principle

Is autocatalytic halogenation reversible?

no

Does Alpha Halogenation happen at more or less sterically hindered positions?

More

What is the Hell-Volhard-Zelinsky Reaction?

The bromination of an alpha carbon on a carboxylic acid.

What are the reagents used for the HVZ reaction?

Br2/PBr3 and THEN H2O

What is the point of PBr3 in the HVZ reaction?

It turns the carboxylic acid into an acid bromide which can undergo the creation of an enol.

Can carboxylic acids turn into enols?

No

Why are alpha-brominated carboxylic acids synthetically useful?

The bromine atom can get substituted for an amine group, creating an Amino Acid

What is the haloform reaction?

Converts methyl ketones into carboxylic acids.

What reagents are used for the haloform reaction?

NaOH, Br2

What happens when you perform haloform reactions in basic conditions?

You polyhalogenate the ketone which then turns into a carboxylic acid

Why do basic conditions haloform reaction create carboxylic acids?

CBr3 is a good leaving group (It's a weak base since the inductive effects of the bromines make the negative charge less effective)

What is an aldal?

An aldehyde with an alcohol group

What are the reagents required to create an aldal?

NaOH, H2O, Methyl Ketones

What is the mechanism for the creation of an aldal?

Deprotonation to create an enolate
Enolate attacks another molecule of the starting product
Protonation

What does it mean when it's said that something is a catalytic reaction?

The reagents are reformed during the reaction

What is the difference between using Ketones and Aldehydes in a Aldal reaction?

Aldehydes shift equilibrium to products, Ketones shift equilibrium to reactants

Is aldol reversable?

Yes

What is it called when an aldol is turned back into a carbonyl?

Retro-Aldol

What is an alpha,beta unsaturated aldehyde?

The product that is formed from the elimination of an aldol.

What reagents are used to cause elimination on an aldol?

Acid and Heat

How does the elimination of an aldol work?

Alpha Carbon deprotonation
Creation of an enolate
Alcohol gets leaving group'd

What drives the aldol elimination reaction to completion?

Entropy

What is the condensation of Aldols?

A reaction where

What is an E1cb mechanism?

A unimolecular elimination conjugate base reaction

What kind of mechanism is an Aldol Condensation?

E1cb?

How can you use temperature to control Aldol Condensation?

Lower temperatures give an alpha-beta Aldol, higher temperatures give an Aldol condensation product.

Can different Aldols react with each other?

Yes

How can you control what product is made from crossed Aldol reactions?

Use a molecule that has no alpha hydrogens and therefore cannot become an enolate.

In an aldol reaction (Condensation or otherwise), what molecule is the nucleophile?

The one that becomes an enolate/attacks the other molecule's carbonyl.

What are the two factors that determine whether or not aldols will react in an addition reaction or a condensation reaction?

Heat = Condensation
If the creation of the double bond would cause tons of conjugation then Condensation will occur.

What is a directed aldol reaction?

An aldol reaction that uses heat to effect what the major product will be.

What base do you use for thermodynamically controlled aldol reactions?

NaOH

What base do you use use for Kinetically controlled Aldol reactions?

LDA

A directed aldol reaction with LDA and cold temperatures will create:

Aldol Addition Products

A directed aldol reaction with LDA and high temperatures will create:

Aldol Condensation Products

When is a directed Aldol synthesis most synthetically useful?

When both Aldols have Alpha Hydrogens

What is the Claisen Condensation?

A reaction in which esters react to create a Beta-Ketone Ester (Alcohol on a beta carbon)

What is the mechanism for Claisen Condensation?

NaOEt creates the Enolate
E1cb on a second ester
Resulting negative charge on an oxygen kicks off the -OR group

What must the product of a Claisen reaction have, and why?

An acidic proton between two carbonyls, because it gets deprotonated by the amount of base present and causes the creation of an enol

What drives the Claisen condensation to completion?

The removal of the acidic proton near the end is thermodynamically preferable.

What are the reagents needed for a Claisen condensation?

NaOEt and H3O+

If the ester used in a Claisen Condensation has a tertiary alpha carbon, will the reaction continue to completion?

No, it NEEDS the acidic proton to prevent the base from reforming the original ester.

What are some restrictions of the Claisen Condensation?

You cannot use Hydroxide as a base, it will just create carboxylic acids.
The base should have the same R group as the ester

Why should the base used in a Claisen Condensation reaction have the same R group as the ester?

It prevents the creation of additional esters + Products

Why should you not use hydroxide as a base in a Claisen condensation?

It will create a carboxylic acid

What is a crossed Claisen condensation?

A claisen condensation between two different esters

What is a Dieckmann cyclization?

A Claisen Condensation wherein a di-ester linear molecule acts as both nucleophile and electrophile, creating cyclic beta-ketone esters

What pKa do esters typically have?

~25

What pKa do alcohols have?

~16

What pKa do ketones typically have?

~16-20

What products do aldol reactions make?

Beta-Hydroxy Ketones

What products do Claisen reactions make?

Beta-Keto Esters

What is the alkylation of enolates?

An enolate acts as a nucleophile in an SN2 reaction with a primary alkyl halide.

Why is alkylation of enolates very difficult?

Polyalkylations

If the halide isn't primary, what happens instead of Sn2?

E2

Can you use Hydroxide or deprotonated alcohols in alkylation of an enolate?

No, they would nuc. attack the alkyl halide

What does the alkylation of enolates produce?

Alpha-Alkyl Carbonyl

What happens when you use LDA in cold temperatures for the alkylation of an enolate?

The alkyl group attaches itself to the less sterically hindered position because LDA is too bulky to get the alpha hydrogen on the more sterically hindered position, which means the less stable enolate forms.

What happens when you use NaH in warmer temperatures for the alkylation of an enolate?

The alkyl group attaches itself to the more sterically hindered position because there's enough energy from the heat to overcome the steric hinderances involved with the formation of the enolate.

Why are diones the best to use for alkylation?

They resist polyalkylation and do not need a strong base.

What is decarboxylation?

The process where if you have a carboxylic acid at a position beta to a carbonyl, it can undergo a concerted intermolecular pericyclic reaction where the carboxylic acid acid leaves and becomes CO2.

What are the reagents for a decarboxylic reaction?

Heat and a beta-carboxylic acid ketone.

What is the aceoacetic acid ester synthesis?

The process of turning Ethyl-acetoacetate into an alpha halide Ketone

What happens in the acetoacetic ester synthesis?

Ethylacetoacetate alkylates to attach an R group via alkyl halides
It undergoes hydrolysis to turn the ester into a carboxylic acid
Heat is applied to turn the whole thing into a ketone