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Gabriel Synthesis

Potassium phthalimide is a ^-NH₂-synthon which allows the preparation of primary amines by reaction with alkyl halides. After alkylation, the phthalimid is not nucleophile and does not react anymore. Product is cleaved by reaction with base or hydrazine, which leads to a stable cyclic product.

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Mechanism of the Gabriel Synthesis

Note: Phthalimide is acidic!

Cleavage:

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Gewald Reaction

The Gewald Reaction is a synthesis of 2-aminothiophenes via a multi-component condensation between sulfur, an α-methylene carbonyl compound and an α-cyanoester.

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Mechanism of the Gewald Reaction

First step in the process is a Knoevenagel Condensation, but the remainder of the sequence is not known in detail:


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Glaser Coupling
Hay Coupling

The Glaser Coupling is a synthesis of symmetric or cyclic bisacetylenes via a coupling reaction of terminal alkynes. Mechanistically, the reaction is similar to the Eglinton Reaction; the difference being the use of catalytic copper(I), which is reoxidized in the catalytic cycle by oxygen in the reaction medium.
The related Hay Coupling has several advantages as compared with the Glaser Coupling. The copper-TMEDA complex used is soluble in a wider range of solvents, so that the reaction is more versatile.

A valuable alternative is the Cadiot-Chodkiewicz Coupling which allows the preparation of asymmetric bisacetylenes.

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Griesbaum Coozonolysis

The Griesbaum Coozonolysis allows the preparation of defined, tetrasubsituted ozonides (1,2,4-trioxolanes) by the reaction of O-methyl oximes with a carbonyl compound in the presence of ozone. In contrast to their traditional role as intermediates in oxidative alkene cleavage, 1,2,4-trioxolanes with bulky substituents are isolable and relatively stable compounds.
The selective synthesis of substituted 1,2,4-trioxolanes has drawn considerable interest following indications that this heterocycle confers potent pharmacologic activity such as in the antimalarial area.

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Mechanism of the Griesbaum Coozonolysis

The unmodified ozonolysis of an unsymmetrical alkene produces the intermediate carbonyl compounds and carbonyl oxides nonselectively; these can then react with each other to give a statistical mixture of 1,2,4-trioxolanes.

A coozonolysis (two compounds in presence of ozone) is possible if one precursor generates the carbonyl oxide in situ that then reacts with the second compound - the carbonyl. N-Methyl oximes have been found to be ideal precursors, because they readily react as dipolarophiles in a 1,3-dipolar cycloaddition with ozone. A retro-1,3-dipolar cycloaddition then leads to the formation of the carbonyl oxide and methyl nitrite:

The 1,3-dipolar cycloaddition of the carbonyl oxide with the carbonyl compound gives tetrasubsituted ozonides:

If no carbonyl compound is added, 1,2,4,5-tetraoxanes might be isolated through dimerization of the carbonyl oxide:


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rignard Reaction
Grignard Reagents

The Grignard Reaction is the addition of an organomagnesium halide (Grignard reagent) to a ketone or aldehyde, to form a tertiary or secondary alcohol, respectively. The reaction with formaldehyde leads to a primary alcohol.
Grignard Reagents are also used in the following important reactions: The addition of an excess of a Grignard reagent to an ester or lactone gives a tertiary alcohol in which two alkyl groups are the same, and the addition of a Grignard reagent to a nitrile produces an unsymmetrical ketone via a metalloimine intermediate. (Some more reactions are depicted below)

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Mechanism of the Grignard Reaction

While the reaction is generally thought to proceed through a nucleophilic addition mechanism, sterically hindered substrates may react according to an SET (single electron transfer) mechanism:

With sterically hindered ketones the following side products are received:
The Grignard reagent can act as base, with deprotonation yielding an enolate intermediate. After work up, the starting ketone is recovered.

A reduction can also take place, in which a hydride is delivered from the β-carbon of the Grignard reagent to the carbonyl carbon via a cyclic six-membered transition state.

Additional reactions of Grignard Reagents:
With carboxylic acid chlorides:

Esters are less reactive than the intermediate ketones, therefore the reaction is only suitable for synthesis of tertiary alcohols using an excess of Grignard Reagent:

With nitriles:

With CO₂ (by adding dry ice to the reaction mixture):

With oxiranes:

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Olefin Metathesis
Grubbs Reaction

Olefin Metathesis allows the exchange of substituents between different olefins - a transalkylidenation.

This reaction was first used in petroleum reformation for the synthesis of higher olefins (Shell higher olefin process - SHOP), with nickel catalysts under high pressure and high temperatures. Nowadays, even polyenes with MW > 250,000 are produced industrially in this way.
Synthetically useful, high-yield procedures for lab use include ring closure between terminal vinyl groups, cross metathesis - the intermolecular reaction of terminal vinyl groups - and ring opening of strained alkenes. When molecules with terminal vinyl groups are used, the equilibrium can be driven by the ready removal of the product ethene from the reaction mixture. Ring opening metathesis can employ an excess of a second alkene (for example ethene), but can also be conducted as a homo- or co-polymerization reaction. The driving force in this case is the loss of ring strain.
All of these applications have been made possible by the development of new homogeneous catalysts. Shown below are some of these catalysts, which tolerate more functional groups and are more stable and easy to handle.

The Schrock catalysts are more active and are useful in the conversion of sterically demanding substrates, while the Grubbs catalysts tolerate a wide variety of functional groups.
The second generation Grubbs catalysts are even more stable and more active than the original versions. Some of these are depicted:

K. Grela, S. Harutyunyan, A. Michrowska, Angew. Chem. Int. Ed., 2002, 114, 4038. DOI

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Mechanism of Olefin Metathesis

Initiation:

Catalytic Cycle:
Chauvin Mechanism