Mannich Reaction
This multi-component condensation of a nonenolizable aldehyde, a primary or secondary amine and an enolizable carbonyl compound affords aminomethylated products. The iminium derivative of the aldehyde is the acceptor in the reaction.
The involvement of the Mannich Reaction has been proposed in many biosynthetic pathways, especially for alkaloids.
Mechanism of the Mannich Reaction
Meerwein-Ponndorf-Verley Reduction
The aluminium-catalyzed hydride shift from the a-carbon of an alcohol component to the carbonyl carbon of a second component, which proceeds via a six-membered transition state, is referred to as the Meerwein-Ponndorf-Verley Reduction (MPV) or the Oppenauer Oxidation, depending on which component is the desired product. If the alcohol is the desired product, the reaction is viewed as the Meerwein-Ponndorf-Verley Reduction.
Isopropanol is useful as a hydride donor because the resulting acetone may be continuously removed from the reaction mixture by distillation.
Grignard Reagents will sometimes yield the result of an MPV reduction if the carbonyl carbon is too hindered for nucleophilic addition.
Michael Addition
The 1,4-addition (or conjugate addition) of resonance-stabilized carbanions. The Michael Addition is thermodynamically controlled; the reaction donors are active methylenes such as malonates and nitroalkanes, and the acceptors are activated olefins such as α,β-unsaturated carbonyl compounds.
Examples:
donors
acceptorsMechanism of the Michael Addition
Oppenauer Oxidation
The aluminium-catalyzed hydride shift from the α-carbon of an alcohol component to the carbonyl carbon of a second component, which proceeds over a six-membered transition state, is named Meerwein-Ponndorf-Verley-Reduction (MPV) or Oppenauer Oxidation (OPP) depending on the isolated product. If aldehydes or ketones are the desired products, the reaction is viewed as the Oppenauer Oxidation.
Non-enolizable ketones with a relatively low reduction potential, such as benzophenone, can serve as the carbonyl component used as the hydride acceptor in this oxidation.
Ozonolysis
Criegee Mechanism
Ozonolysis allows the cleavage of alkene double bonds by reaction with ozone. Depending on the work up, different products may be isolated: reductive work-up gives either alcohols or carbonyl compounds, while oxidative work-up leads to carboxylic acids or ketones.
Mechanism of Ozonolysis
The mechanism was suggested by Criegee (Angew. Chem. Int. Ed., 1975, 87, 745.) and has been recently revisited using 17O-NMR Spectroscopy by the Berger Group (Eur. J. Org. Chem., 1998, 1625.).First step is a 1,3-dipolar cycloaddition of ozone to the alkene leading to the primary ozonide (molozonide, 1,2,3-trioxolane, or Criegee intermediate) which decomposes to give a carbonyl oxide and a carbonyl compound:
The carbonyl oxides are similar to ozone in being 1,3-dipolar compounds, and undergo 1,3-dipolar cycloaddition to the carbonyl compounds with the reverse regiochemistry, leading to a mixture of three possible secondary ozonides (1,2,4-trioxolanes):
These secondary ozonides are more stable than primary ozonides. Even if the peroxy bridge is shielded by steric demanding groups leading to isolable products, they should not be isolated from an unmodified ozonolysis, because still more explosive side products (tetroxanes) may have been formed:
As endoperoxides are investigated as antimalarial compounds, more selective methods have been developed for their preparation. Some reactions can be found here: V. D.B. Bonifacio, Org. Chem. Highlights 2004, October 25.
The Criegee mechanism is valid for reactions in hydrocarbons, CH2Cl2, or other non-interactive solvents. Alcohols react with the carbonyl oxide to give hydroperoxy hemiacetals:
The synthetic value lies in the way the complex mixtures of intermediates can be worked up to give a defined composition of products and a clean conversion of all peroxide species. The three main possibilities are given above, along with examples for the reagents used.
Pechmann Condensation
Coumarin Synthesis
The Pechmann Condensation allows the synthesis of coumarins by reaction of phenols with β-keto esters.
Mechanism of the Pechmann Condensation
The reaction is conducted with a strong Brønstedt acid such as methanesulfonic acid or a Lewis acid such as AlCl3. The acid catalyses transesterification as well as keto-enol tautomerisation:
A Michael Addition leads to the formation of the coumarin skeleton. This addition is followed by rearomatisation:
Subsequent acid-induced elimination of water gives the product:
Pinacol Rearrangement
In the conversion that gave its name to this reaction, the acid-catalyzed elimination of water from pinacol gives t-butyl methyl ketone.
Mechanism of the Pinacol Rearrangement
This reaction occurs with a variety of fully substituted 1,2-diols, and can be understood to involve the formation of a carbenium ion intermediate that subsequently undergoes a rearrangement. The first generated intermediate, an α-hydroxycarbenium ion, rearranges through a 1,2-alkyl shift to produce the carbonyl compound. If two of the substituents form a ring, the Pinacol Rearrangement can constitute a ring-expansion or ring-contraction reaction.
Reformatsky Reaction
The formation of ester-stabilized organozinc reagents and their addition to carbonyl compounds
Mechanism of the Reformatsky Reaction
Organozinc compounds are prepared from α-halogenesters in the same manner as Grignard Reagents. This reaction is possible due to the stability of esters against organozincs. Due to the very low basicity of zinc enolates, there is hardly any competition from proton transfer, and the scope of carbonyl addition partners is quite broad. In presence of ketones or aldehydes, the organozinc compounds react as the nucleophilic partner in an addition to give β-hydroxy esters.
An ester-stabilized organozinc reagentRobinson Annulation
The Robinson Annulation is a useful reaction for the formation of six-membered rings in polycyclic compounds, such as steroids. It combines two reactions: the Michael Addition and the Aldol Condensation
Mechanism of the Robinson Annulation
The first step in the process is the Michael Addition to an α,β-unsaturated ketone, such as methyl vinyl ketone:
The newly formed enolate intermediate must first tautomerize for the conversion to continue:
The subsequent cyclization via Aldol Addition is followed by a condensation to form a six-membered ring enone:
The Robinson Annulation can also proceed under acidic catalysis, with the entire process occurring in one pot, as shown below. The use of a precursor of the α,β-unsaturated ketone, such as a β-chloroketone, can reduce the steady-state concentration of enone and decrease the side reaction of polymerization.
a) C. H. Heathcock, J. E. Ellis, J. E. McMurry, A. Coppolino, Tetrahedron Lett., 1971, 12, 4995.
b) C. H. Heathcock, C. Mahaim, M. F. Schlecht, T. Utawanit, J. Org. Chem., 1984, 49, 3264.
Rosenmund Reduction
The catalytic hydrogenation of acid chlorides allows the formation of aldehydes.
Mechanism of the Rosenmund Reduction
Side products:
The Pd catalyst must be poisoned, for example with BaSO4, because the untreated catalyst is too reactive and will give some overreduction. Some of the side products can be avoided if the reaction is conducted in strictly anhydrous solvents.
