Subject Chemistry
Paper No and Title 9: Organic Chemistry –III (Reaction Mechanism –II)
Module No and Title 14: Addition of organozinc and organolithium reagents to carbonyl Module Tag CHE_P9_M14
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
TABLE OF CONTENTS
1. Learning Outcomes 2. Introduction 3. Organolithium Chemistry 4. Organozinc Chemistry 5. Summary
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
1. Learning Outcomes
After studying this module, you shall be able to
Identify organometallic reagents. Learn to make C-C bonds via organometallic reagents. Comprehend and apply the role of organolithium reagent for C-C bond formation Know the use of Organozinc reagents in various reactions.
2. Introduction
Organometallic Chemistry
Formation of organic molecules is basically the formation of C-C bonds and one of the most convenient methods to do so is the use of organometallics, such as Grignard reagent and organolithiums.
The organomettalic reagents have metal carbon bond which is polar. The metal being electropositive in nature imparts electron richness on the carbon directly attached to the metal in the organomettalic reagent.
The organometallic reagents are used as nucleophiles to attack on electrophilic centers. The polarity of a covalent bond between two different elements is determined by electronegativity. Let us understand this with the help of carbonyl compound being attacked by organometallic reagent e.g., methyl lithium. In the carbonyl group, the oxygen is more electronegative than carbon that makes the carbon of carbonyl group as electron deficient and hence acts as an electrophilic center. In methyl lithium, lithium is electropositive and imparts electron richness on the carbon of methyl, which can attack as a nucleophile on the electron deficient carbonyl carbon.
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
Thus, in organo lithium, the organic part acts as nucleophile. Similarly in organozinc, zinc is lectropositive but not as much as lithium in organolithiums or magnesium in Grignard reagent. Let us study them in detail.
3. ORGANOLITHIUM CHEMISTRY
As discussed earlier also, lithium is a very electropositive metal and the Li-C bond is highly polarized towards carbon. The carbon in organolithiums is thus highly nucleophilic which can attack on carbonyl group to yield alcohols as the most common examples.
Mechanism :
The organic part i.e the alkyl group of organolithium acts as a nucleophile and attcks on the carbonyl carbon resulting in the alkoxide formation. On subsequent hydrolysis with water, the alkoxide gets protonated and results in the formation of alcohol.
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
In the nucleophilic attack of organolithium, let us try to understand which orbitals are used?
The HOMO Li-C sigma bond which is polarized towards carbon attcks on the carbonyl carbon.
Note that these reactions are very similar to the reaction of carbonyl with Grignard reagent.
Examples:
1. Addition to formaldehyde gives 10 alcohols.
2. Addition to aldehydes gives 20 alcohols.
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
3. Addition to ketones gives 30 alcohols
4. Addition to aromatic aldehyde.
5. Addition to aromatic ketones.
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
6. Addition to carbon dioxide forms a carboxylic acid.
4. ORGANOZINC CHEMISTRY
Organozinc compounds contain carbon bonded to zinc. These compounds are less reactive than other equivalent organometallic reagents, such as organolithium reagents and Grignard reagents.
In organozinc compounds, the zinc being electropositive imparts electron richness to the directly attached carbon of the organic part. Let us understand this with the help of two named reactions, Reformatsky reaction and Simmons-Smith reaction.
4.1 Reformatsky Reaction
In this reaction an α-haloester is treated with an aldehyde (or ketone) in the presence of zinc and subsequently followed by acidification, the product obtained is a β-hydroxyester.
The general reaction can be represented as follows:
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
Mechanism:
It involves the formation of an organozinc reagent which provides electron richness at the α-carbon where halogen was there. This is rearranged in the enolate form and acts as a nucleophile on the carbonyl carbon in a very similar manner as in aldol condensation.
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
Step 1: Formation of organozinc enolate : Oxidative addition of metal zinc to carbon-halogen bond which results in the formation of a carbon-zinc enolate.This rearranges to the Oxygen-Zinc enolate via coordination.
Step 2: The organozinc enolate attacks as a nucleophile on the carbonyl carbon of the aldehyde (or ketone) and results in formation of a new carbon-carbon bond.
Step 3: The alkoxide attached to ZnBr gets protonated by the acidification resulting in the formation of β-hydroxyester.
Note that the ester group is not hydrolysed in this mild acidification.
Examples:
1. Ethyl-2-bromoactetae(I) reacts with cyclohexanone (II) in the presence of zinc followed by acidification result in the corresponding a β-hydroxyester (III)
(I) (II) (III)
2. Ethyl-2-bromoactetae (IV) reacts with benzaldehyde(V) in the presence of zinc followed by acidification results in the corresponding a β-hydroxyester (VI)
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
(IV) (V) (VI)
The following reactions are recent contributions to Reformatsky reaction:
An operationally simple and very efficient Reformatsky reaction of aldehydes has been carried out in THF in the presence of low valent iron or copper which were prepared in situ employing a bimetal redox strategy through reduction of Fe(III) or Cu(II) salts with magnesium.
Titanocene(III)-Promoted Reformatsky Additions
Bisoxazolidine-Catalyzed Enantioselective Reformatsky Reaction
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
In- or In(I)-Employed Tailoring of the Stereogenic Centers in the Reformatsky-Type Reactions of Simple Ketones, α-Alkoxy Ketones, and β-Keto Esters
Double Reformatsky Reaction: Divergent Synthesis of δ-Hydroxy-β-ketoesters
Efficient Synthesis of 2-Amino Acid by Homologation of β2-Amino Acids Involving the Reformatsky Reaction and Mannich-Type Imminium Electrophile
High Chelation Control of Three Contiguous Stereogenic Centers in the Reformatsky Reactions of Indium Enolates with α-Hydroxy Ketones: Unexpected Stereochemistry of Lactone Formation.
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
4.2 Simmons-Smith Reaction
The Simmons-Smith reagent is used to prepare cyclopropanes from olefins using methylene iodide as the methylene source in the presence of zinc. An intermediate, carbenoid (iodomethyl) zinc iodide is generated as an organozinc reagent in this reaction. This intermediate further reacts with alkenes to form the cyclopropanated product.
Example,
Step 1: generation of cyclopropanating species
Step 2: Cycloproapnation transition step
General features of the reaction as reported by Simmon-Smith:
Reaction is very dependent on the Zn(Cu) couple
Cyclopropanation is stereospecific CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl
Proximal ethers can facilitate the reaction
5. Summary
Organometallic compounds are compounds, which have carbon-metal bond. The carbon-metal bond is highly polarized. Organolithium reagents are organometallic compounds that contain carbon – lithium bonds. The carbon in organolithium reagents is highly nucleophilic and attacks the carbonyl group to give alcohols. Organozinc compounds contain carbon - zinc bonds. The organozinc compounds are less reactive than other equivalent organometallic reagents, such as organolithium reagents and Grignard reagents.
CHEMISTRY PAPER: 9 , Organic Chemistry- III (Reaction Mechanisms- II) MODULE: 14, Addition of organozinc and organolithium reagents to carbonyl