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Aldol Reaction ORGANIC SYNTHESIS CHE 416 BY ADEWUYI Adewale Chemical Sciences Redeemer’s University This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. 1: Aldol reaction • Aldol reaction is a means of forming carbon– carbon bonds in organic chemistry. It unites two relatively simple molecules into a more complex one. • Aldol' is an abbreviation of aldehyde and alcohol. When the enolate of an aldehyde or a ketone reacts at the α-carbon with the carbonyl of another molecule under basic or acidic conditions to obtain β-hydroxy aldehyde or ketone, this reaction is called Aldol Reaction. • Increased complexity arises because up to two new stereogenic centers are formed (modern methods are being developed with high yield). Hypothetical example Mechanism of the Aldol Addition Aldol Condensation In some cases, the adducts obtained from the Aldol Addition can easily be converted (in situ) to α,β-unsaturated carbonyl compounds, either thermally or under acidic or basic catalysis. The formation of the conjugated system is the driving force for this spontaneous dehydration. Under a variety of protocols, the condensation product can be obtained directly without isolation of the aldol. Mechanism of the Aldol Condensation 2: Alder-Ene Reaction/Ene reaction The ene reaction (also known as the Alder-ene reaction) is a chemical reaction between an alkene with an allylic hydrogen(the ene) and a compound containing a multiple bond (the enophile), in order to form a new σ-bond with migration of the ene double bond and 1,5 hydrogen shift. The product is a substituted alkene with the double bond shifted to the allylic position Mechanism of the Alder-Ene Reaction 3: Azo Coupling Azo coupling is the most widely used industrial reaction in the production of dyes, lakes and pigments. Aromatic diazonium ions acts as electrophiles in coupling reactions with activated aromatics such as anilines or phenols. The substitution normally occurs at the para position, except when this position is already occupied, in which case ortho position is favoured. The pH of solution is quite important; it must be mildly acidic or neutral, since no reaction takes place if the pH is too low. Mechanism of Azo Coupling 4: Beckmann Rearrangement The Beckmann rearrangement is an acid-catalyzed rearrangement of an oxime to an amide. Cyclic oximes yield lactams. Mechanism of the Beckmann Rearrangement 5: Acetoacetic-Ester Condensation/Claisen Condensation The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone Reaction mechanism Claisen Rearrangement The aliphatic Claisen Rearrangement is a [3,3]-sigmatropic rearrangement in which an allyl vinyl ether is converted thermally to an unsaturated carbonyl compound. Mechanism Variations All Claisen rearrangement reactions described to date require temperatures of > 100 °C if uncatalyzed. The observation that electron withdrawing groups at C-1 of the vinyl moiety exert a positive influence on the reaction rate and the yield has led to the development of the following variations: Aromatic Claisen rearrangement The first reported Claisen rearrangement is the [3,3]-sigmatropic rearrangement of an allyl phenyl ether to intermediate 1, which quickly tautomerizes to an ortho-substituted phenol. Meta-substitution affects the regioselectivity of this rearrangement. For example, electron withdrawing groups (e.g. bromide) at the meta-position direct the rearrangement to the ortho-position (71% ortho-product), while electron donating groups (e.g. methoxy), direct rearrangement to the para-position (69% para-product). Additionally, presence of ortho- substituents exclusively leads to para-substituted rearrangement products (tandem Claisen and Cope rearrangement) Bellus–Claisen rearrangement The Bellus–Claisen rearrangement is the reaction of allylic ethers, amines, and thioethers with ketenes to give γ,δ-unsaturated esters, amides, and thioesters Eschenmoser–Claisen rearrangement The Eschenmoser–Claisen rearrangement proceeds by heating allylic alcohols in the presence of N,N-dimethylacetamide dimethyl acetal to form γ,δ-unsaturated amide Mechanism Ireland–Claisen rearrangement The Ireland–Claisen rearrangement is the reaction of an allylic carboxylate with a strong base (such as lithium diisopropylamide) to give a γ,δ-unsaturated carboxylic acid. The rearrangement proceeds via silylketene acetal, which is formed by trapping the lithium enolate with chlorotrimethylsilane. Like the Bellus-Claisen (above), Ireland-Claisen rearrangement can take place at room temperature and above. Johnson–Claisen rearrangement The Johnson–Claisen rearrangement is the reaction of an allylic alcohol with an orthoester to yield a γ,δ-unsaturated ester. Weak acids, such as propionic acid, have been used to catalyze this reaction. This rearrangement often requires high temperatures (100 to 200 °C) and can take anywhere from 10 to 120 hours to complete. Mechanism Photo-Claisen rearrangement The photo-Claisen rearrangement proceed through radical mechanism. Aryl ethers undergo the photo-Claisen rearrangement. 6: Clemmensen Reduction The Clemmensen Reduction allows the deoxygenation of aldehydes or ketones, to produce the corresponding hydrocarbon. It is a chemical reaction described as a reduction of ketones (or aldehydes) to alkanes using zinc amalgam and hydrochloric acid Mechanism of the Clemmensen Reduction The reduction takes place at the surface of the zinc catalyst. In this reaction, alcohols are not postulated as intermediates, because subjection of the corresponding alcohols to these same reaction conditions does not lead to alkanes. The following proposal employs the intermediacy of zinc carbenoids to rationalize the mechanism of the Clemmensen Reduction: 7: Dieckmann Condensation Dieckmann condensation is the intramolecular chemica reaction of diesters with base to give β-ketoesters Reaction Mechanism Deprotonation of an ester at the α-position generates an enolate ion which then undergoes a 5-exo-trig nucleophilic attack to give a cyclic enol. Protonation with a Bronsted-Lowry + acid (H3O for example) re-forms the β-keto ester. Owing to the steric stability of five- and six- membered ring structures, these will preferentially be formed. So 1,6 diesters will form five- membered cyclic β-keto esters, while 1,7 diesters will form six-membered β-keto esters. 8: Diels-Alder Reaction The Diels–Alder reaction is an organic chemical reaction (specifically, a [4+2] cycloaddition) between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The [4+2]-cycloaddition of a conjugated diene and a dienophile (an alkene or alkyne), an electrocyclic reaction that involves the 4 π-electrons of the diene and 2 π-electrons of the dienophile. The driving force of the reaction is the formation of new σ-bonds, which are energetically more stable than the π-bonds. Mechanism of the Diels-Alder Reaction The reaction is diastereoselective. 9: Friedel-Crafts reactions The Friedel–Crafts reactions are a set of reactions developed to attach substituents to an aromatic ring. There are two main types of Friedel–Crafts reactions: alkylation reactions and acylation reactions. Both proceed by electrophilic aromatic substitution. A: Friedel-Crafts Acylation This electrophilic aromatic substitution allows the synthesis of monoacylated products from the reaction between arenes and acyl chlorides or anhydrides. The products are deactivated, and do not undergo a second substitution. Mechanism of the Friedel-Crafts Acylation B: Friedel-Crafts Alkylation This Lewis acid-catalyzed electrophilic aromatic substitution allows the synthesis of alkylated products via the reaction of arenes with alkyl halides or alkenes. Mechanism of the Friedel-Crafts Alkylation Using alkyl halide Using alkenes 10: Michael Addition The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C–C bonds. 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. In this scheme the R and R' substituents on the nucleophile (a Michael donor) are electron- withdrawing groups such as acyl and cyano making the methylene hydrogen acidic forming the carbanion on reaction with base B:. The substituent on the activated alkene, also called a Michael acceptor, is usually a ketone making it an enone, but it can also be a nitro group. Examples of donors Examples of acceptors Mechanism of the Michael Addition 11: Pechmann Condensation The Pechmann condensation is a synthesis of coumarins, starting from a phenol and a carboxylic acid or ester containing a β-carbonyl group (β-keto esters). This is carried out under strong acidic condition. 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 The mechanism involves an esterification/transesterification followed by attack of the activated carbonyl ortho to the oxygen to generate the new ring. The final step
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