Step-by-Step Guide to the Reformatsky Reaction Mechanism
What is the Reformatsky Reaction?
The name Reformatsky reaction is kept in the honour of a Russian chemist named Sergey Nikolaevich Reformatsky, who discovered this reaction in 1887. This is a reaction that takes place between a carbonyl compound and an alpha‐half ester, which can be an aldehyde, an ester, or a ketone. This reaction takes place mostly in the presence of zinc. This represents the extended reactions between the carbonyl compounds either with an alkyl zinc halide or a dialkylzinc.
Advantage of Reformatsky Reaction Process
An advantage of this reaction is that the organozinc compound isolation is not required. At the time of the reaction process, a new carbon‐carbon linkage can be created along with an organozinc halide formation and the decomposition because of the presence of dilute acids.
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Generally, the Reformatsky reaction yields are improved if the reaction is carried out in 2 steps.
Firstly, the alpha Bromo ester can be converted into an organozinc bromide
By reaction with the zinc compound in pure and dry dimethoxyethane.
This derivative is formed apparently almost in the quantitative yield.
Reformatsky Reaction Definition
According to the general definition, the Reformatsky reaction can be described as an organic reaction used to convert an aldehyde or ketone and α-haloester to a β-hydroxy ester with the help of acid workup and metallic zinc. Here, an inert solvent such as THF (tetrahydrofuran) or diethyl ether is often used as a reaction solvent.
The carbonyl compound’s condensation reaction, along with the alpha haloester in the presence of zinc metal, is referred to as the Reformatsky reaction.
The solvent that is most often used in this reaction is given as ether or benzene or a benzene ether mixture.
Structure of the Reagent
The THF’s complexes crystal structures of Reformatsky reagents ethyl bromozincacetate and tert-butyl bromozincacetate have been determined. These both form cyclic 8-membered dimers in the solid-state but vary in stereochemistry. The 8-membered ring in the ethyl derivative adopts a conformation of tub-shaped and contains cis THF ligands and cis Bromo groups. Whereas, in the derivative of tert-butyl, the ring exists in a chair form and the THF ligands and Bromo groups are the trans.
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Reformatsky Mechanism
Let us look at how the reaction takes place and what happens while the reaction occurs.
Generally, the Reformatsky reaction commences either with the oxidative insertion or zinc addition into the carbon-halogen bond of an α-haloester.
The primary purpose of using zinc is to allow the enolate generation even without using the Bronsted base, which generally condenses either with the aldehyde or ketone itself.
After the insertion happens, the compounds get coordinated with each other leading to a dimer formation. Also, this compound further experiences a rearrangement that results in the emergence of 2 zinc enolates.
After that, the oxygen of the aldehyde or ketone coordinates to the zinc, and a new rearrangement takes place where the 2 reagents now contain a carbon-carbon bond between them.
Following that, an acid workup splits the oxygen bond and zinc to generate β-hydroxy ester and zinc(II) salt as the final products.
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On an important note, the α-hydroxy esters product are the essential substances that are required for natural product synthesis and in the pharmaceutical industry.
Identifying the First-order Reaction
First-order reactions are when the reaction rate at any provided time is directly proportional to the reactant’s concentration left at that specific time or the active mass.
The rate law is expressed as R=K[A]
Let us look at some typical ways to identify it:
These types of reactions take forever to get completed finally.
The reaction rate decreases exponentially as the time slows down.
The sample half-life is simply a constant value. After each half-life, the reactant amount gets halved.
The half-life and rate constant are inversely proportional, and none of which depends on the sample’s initial concentration.
A graph between the time and logarithm of the concentration of the reactant left forms a straight line.
Advantages of Reformatsky Reaction
A few of the significant advantages of this reaction can be listed as follows:
The reformatsky reaction is conducted using highly hindered ketones. This reaction also facilitates the successful addition of nucleophiles to the ketone’s delta positive carbon atom.
Reformatsky mechanism can be adapted easily for the intramolecular aldol reactions.
The organozinc halide reagents, which are used in the Reformatsky Reaction, are considered relatively stable and are also available commercially.
Reformatsky reaction results in the beta-hydroxy ester’s isolation.
Another merit of the Reformatsky reaction can be given as the convenience since the reaction is an alternative to the reaction of a ketone or an aldehyde with the preferred lithium enolate of an ester.
The yields of Reformatsky were improved with freshly prepared zinc powder, a heated column of zinc dust, acid-washed zinc, trimethylchlorosilane, and copper-zinc couple.
FAQs on Reformatsky Reaction Explained: Mechanism, Uses & Examples
1. What is the Reformatsky reaction in organic chemistry?
The Reformatsky reaction is an organic chemical reaction used to form a carbon-carbon bond. It involves the reaction of an aldehyde or ketone with an α-halo ester in the presence of activated zinc metal. The final product of this reaction, after an acidic workup, is a β-hydroxy ester.
2. What are the essential starting materials and reagents for a Reformatsky reaction?
To carry out a Reformatsky reaction, you need the following key components:
- A carbonyl compound, which can be either an aldehyde or a ketone.
- An α-halo ester, such as ethyl bromoacetate.
- Finely divided or activated zinc metal, which initiates the reaction.
- An aprotic solvent, typically diethyl ether or tetrahydrofuran (THF), to provide the reaction medium.
3. Can you provide a simple example of the Reformatsky reaction?
A classic example is the reaction between acetone (a ketone) and ethyl bromoacetate (an α-halo ester). In the presence of zinc metal and a solvent like THF, followed by a mild acid workup (H₃O⁺), the reaction yields ethyl 3-hydroxy-3-methylbutanoate, which is a β-hydroxy ester.
4. What is the mechanism of the Reformatsky reaction?
The mechanism proceeds in three main steps:
- Step 1: The zinc metal inserts itself into the carbon-halogen bond of the α-halo ester, forming an organozinc compound known as a Reformatsky reagent or an enolate.
- Step 2: This reagent then acts as a nucleophile and attacks the electrophilic carbonyl carbon of the aldehyde or ketone.
- Step 3: A final acidic workup protonates the resulting alkoxide to give the final product, a β-hydroxy ester.
5. Why is zinc metal specifically used in the Reformatsky reaction and not a more reactive metal like magnesium?
Zinc is used because the organozinc reagent it forms is moderately reactive. It is reactive enough to attack aldehydes and ketones but generally not reactive enough to react with the ester group of another molecule. If a more reactive metal like magnesium were used (as in a Grignard reaction), the resulting reagent would be too reactive and could attack the ester group, leading to unwanted side products and lower yields.
6. How does the Reformatsky reaction differ from an Aldol condensation?
While both reactions form β-hydroxy carbonyl compounds, they differ significantly. The Reformatsky reaction uses a pre-formed organozinc reagent from an α-halo ester to attack a carbonyl group, producing a β-hydroxy ester. In contrast, the Aldol condensation uses a base or acid to form an enolate from an aldehyde or ketone, which then attacks another molecule of the same or different carbonyl compound, producing a β-hydroxy aldehyde or ketone.
7. What are the primary applications or importance of the Reformatsky reaction?
The main importance of the Reformatsky reaction lies in its ability to reliably synthesise β-hydroxy esters. These products are highly valuable intermediates in organic synthesis. For instance, they can be easily dehydrated to form α,β-unsaturated esters, which are important building blocks for more complex molecules, including many natural products and pharmaceuticals.
8. What happens if water is present during the formation of the Reformatsky reagent?
The presence of water or any protic solvent would be detrimental to the reaction. The organozinc reagent (Reformatsky reagent) is a strong base. It would immediately react with the acidic proton of water in an acid-base reaction, destroying the reagent before it has a chance to attack the intended aldehyde or ketone. This is why the reaction must be carried out under anhydrous (dry) conditions using an aprotic solvent.
