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Complete Guide To The Condensations and Alpha Substitutions of Carbonyl Compounds (Enol and Enolate)

Table of Contents:



Enols and Enolate Ions

An alpha carbon is a carbon that neighbors a carbonyl group ( C=O). An alpha hydrogen is a hydrogen that is attached to the alpha carbon. An alpha hydrogen is acidic because when it is removed, the resulting enolate ion is resonance stabilized. In this chapter, we will focus primarily on the reactions that involve alpha hydrogen, and specifically formation of enol or enolate ion. Keto-enol tautomerism is an in isomerization where keto form is converted into enol (en= double bond, ol =alcohol) form.


Keto-Enol Tautomers In Acid And Base
Keto-Enol Tautomers In Acid And Base

Alpha Halogenation of Carbonyl Compounds


Acid Catalyzed Alpha Halogenation

In acid catalyzed halogenation, a ketone reacts with X2 (Cl2, Br2, or I2) under acidic conditions. To predict the product, we simply need to replace alpha hydrogen with the halogen.


Base Catalyzed Alpha Halogenation

In base catalyzed halogenation, a ketone reacts with X2 (Cl2, Br2, or I2) under basic conditions (OH-). In the product we need to replace all of the alpha hydrogens with halogens.




The Haloform Reaction

Haloform reaction uses the same reactants as base catalyzed halogenation.


Mechanism of Haloform reaction

Mechanism of Haloform reaction
Mechanism of Haloform reaction


Alpha Bromination of Acids: The HVZ Reaction

Hell–Volhard–Zelinsky (HVZ) reaction replaces a hydrogen atom with a bromine atom on the alpha carbon of a carboxylic acid.


Hell–Volhard–Zelinsky (HVZ) reaction
Hell–Volhard–Zelinsky (HVZ) reaction

Alkylation of Enolate Ions

LDA is a very strong base that converts the ketone entirely to its enolate and is used to add an alkyl group on the alpha carbon.

Alkylation of Enolate Ions
Alkylation of Enolate Ions

Formation and Alkylation of Enamines

This reaction is useful in adding alkyl groups to the alpha carbon (carbon next to the C=O group) of an aldehyde or ketone.

First, a ketone or an aldehyde is converted into an enamine. An enamine can serve as a great tool to add alkyl groups to the alpha carbon. It can then be taken off to give ketone or aldehyde back.




Aldol Reaction


Aldol reaction is one of the most important reactions in this chapter and in semester 2 of organic chemistry. This reaction can occur under basic or acidic conditions.


Under Basic conditions

Mechanism for Base Catalyzed Aldol Condensation
Mechanism for Base Catalyzed Aldol Condensation

Under Acidic conditions



Mayya's Trick: How to predict the product of Aldol Condensation

  1. Draw two molecules of the starting material and align =O of one with alpha carbon of the other

  2. Get rid of =O and connect the carbon that had =O with the alpha carbon on another molecule through a double bond


Trick: How to predict the product of Aldol Condensation
Trick: How to predict the product of Aldol Condensation

There is also Crossed and Intramolecular Aldol Reactions. Crossed aldol is when instead of attacking itself, the enol or enolate attack another molecule of ketone or aldehyde. Intramolecular aldol is when one end of the molecule attacks another end of the molecule, forming a ring.


Mayya's Trick on how to predict reactants if the product of aldol condensation is given



Claisen and Diekmann Condensations

I think of Claisen condensation as a reaction that is similar to aldol condensation but with esters.


We will recognize Claisen reaction because we will see an ester as a reactant and -OR as the reagent where OR on the nucleophile is the same as OR group on the reactant.

Claisen condensation mechanism
Claisen condensation mechanism

The step in Claisen reaction where the base takes off a double alpha hydrogen is a very important step because this step drives the reaction in the forward direction.


Mayya's trick on predicting the product of Claisen Condensation


Dieckmann condensation refers to an intramolecular clause condensation where one part of the molecule attacks another part of the same molecule.

Crossed Claisen can also occur between two different esters.



How to predict reactants if the product of Claisen condensation is given




Hydrolysis and Decarboxylation of b-Ketoesters

Decarboxylation occurs where there is a carboxylic acid group (COOH) one carbon away from a carbonyl group (C=O). Under heat conditions, COOH leaves the molecule becoming carbon dioxide.

Beta keto ester can be converted into a carboxylic acid and undergo decarboxylation after with the aid of heat.


Hydrolysis and Decarboxylation of b-Ketoesters
Hydrolysis and Decarboxylation of b-Ketoesters


Malonic Ester Synthesis

Malonic ester synthesis starts with a molecule called malonic ester. The product of malonic ester synthesis is a carboxylic acid with one or two alkyl groups added to the alpha carbon.


Malonic Ester Synthesis
Malonic Ester Synthesis

Let's try a synthesis example.

Acetoacetic Ester Synthesis

Acetoacetic ester synthesis is almost the same as malonic ester synthesis. The difference is that instead of malonic ester, it starts with an acetoacetic ester. The product of acetoacetic ester synthesis is methyl ketone with one or two alkyl groups on the alpha carbon.



Conjugate Addition to alpha,beta-Unsaturated Carbonyl Compounds (Michael)

Alpha,beta -unsaturated carbonyl compounds are not only the products of Aldol condensation but can also serve as reactants in a reaction called Michael (also called 1,4 addition).



Michael reaction mechanism
Michael reaction mechanism

The nucleophiles are most often enolate anions, although other nucleophiles can add as well.


Decarboxylation can follow.


How to predict the product of Michael reaction

Mayya's Trick


  1. Identify alpha beta unsaturated ketone or aldehyde (Molecule A) and label alpha and beta carbons

  2. Identify alpha carbon on the other molecule (Molecule B)

  3. Connect the alpha carbon of B to the beta carbon of A. Get rid of the alpha, beta double bond.

Let's take a look at different possible Michael nucleophiles and nucleophile acceptors.

Michael reaction nucleophiles and acceptors
Michael reaction nucleophiles and acceptors

Organocuprate or Gilman reagent adds R group to the beta carbon of Michael as well.


Organocuprate (Gilman) reaction with Michael
Organocuprate (Gilman) reaction with Michael

Grignard or Organolithium Reaction with Michael


Robinson Annulation

Robinson Annulation is two reactions combined. It is Michael reaction followed by intramolecular Aldol condensation.

Mayya's Trick

How to predict reactants when Robinson Annulation Product is Given

  1. Identify double single double bond O

  2. identify the alpha and beta carbons

  3. break between alpha and beta and attach =O to the beta carbon

  4. identify 1,5 =O and number the carbons 1 through 5

  5. Break between carbon between carbons 3 and 4 and put a double bond between carbons 2 and 3 (if that doesn't work you might have to number carbons in the opposite direction)


How to predict reactants when Robinson Annulation Product is Given
How to predict reactants when Robinson Annulation Product is Given

Crossed Enolate Reactions Using LDA

LDA is a very strong base and a poor nucleophile. It is often used to generate enolate ions from carbonyl compounds such as ketones, aldehydes and esters. These enolate ions can further undergo aldol reaction.


Notes and Tricks

This chapter is considered one of the hardest chapters in the second semester of organic chemistry. It is often difficult for students to recognize which reaction they are dealing with or how to synthesize a certain compound. I have created some tricks to help you with this chapter!


Mayya's Trick

How To Recognize The Products Of Reactions In This Chapter




Mayya's Trick

How to predict reactants when Claisen product is given

  1. Find alpha and beta carbons from the ester group

  2. Break the bond between alpha and beta carbons

  3. Attach OR (look at the base used) to the beta carbon


How to predict reactants when Claisen product is given
How to predict reactants when Claisen product is given

Mayya's Trick

How to predict reactants when Aldol product (α,β unsaturated carbonyl) is given

  1. Identify alpha (next to C=O) and beta (next to alpha) carbons

  2. break the bond between them

  3. add =O to the beta carbon

How to predict reactants when Aldol product (β hydroxy ketone) is given

  1. Identify alpha (next to C=O) and beta (next to alpha) carbons

  2. break the bond between them

  3. Turn OH on beta carbon into =O


How to predict reactants when Aldol product is given
How to predict reactants when Aldol product is given

Mayya's Trick

How to predict reactants when Michael product is given

  1. Find 1,5 diketone

  2. Number 1 through 5

  3. Break between 2 and 3

  4. Put double bond between 3 and 4


How to predict reactants when Michael product is given
How to predict reactants when Michael product is given

Finally, let's learn how to recognize what reactions we are dealing with in order to predict the products correctly.



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