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Home , Aldol reaction, Sarett oxidation

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 . It unites two relatively simple into a more complex one. • Aldol' is an abbreviation of and . When the of an aldehyde or a reacts at the α-carbon with the carbonyl of another 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 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 . 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 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- Condensation/

The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two 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 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- exclusively leads to para-substituted rearrangement products (tandem Claisen and Cope rearrangement) Bellus–Claisen rearrangement The Bellus–Claisen rearrangement is the reaction of allylic , , and thioethers with ketenes to give γ,δ-unsaturated esters, amides, and thioesters Eschenmoser–Claisen rearrangement The Eschenmoser–Claisen rearrangement proceeds by heating allylic 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 diisopropylamide) to give a γ,δ-unsaturated . 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 or , 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 . 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 or Michael addition is the of a or another 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 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- (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 is a dehydration, as seen following an aldol condensation. 12: Suzuki Coupling The Suzuki reaction is an , classified as a coupling reaction, where the coupling partners are a boronic acid and an organohalide catalyzed by a palladium(0) complex

It is widely used to synthesize poly-olefins, styrenes, and substituted biphenyls. Reaction mechanism According to the scheme shown below, the mechanism can be achieved in three stages which are: 1- Oxidative addition: In most cases the oxidative Addition is the rate determining step of the catalytic cycle. During this step, the palladium catalyst is oxidized from palladium(0) to palladium(II). The palladium catalyst 1 is coupled with the alkyl halide 2 to yield an organopalladium complex 3. As seen in the diagram below, the oxidative addition step breaks the carbon-halogen bond where the palladium is now bound to both the halogen and the R group. 2- Transmetalation: Transmetalation is an organometallic reaction where ligands are transferred from one species to another. In the case of the Suzuki coupling the ligands are transferred from the organoboron species 6 to the palladium(II) complex 4 where the base that was added in the prior step is exchanged with the R1 substituent on the organoboron species to give the new palladium(II) complex 8. 3- Reductive elimination: The final step is the reductive elimination step where the palladium(II) complex (8) eliminates the product (9) and regenerates the palladium(0) catalyst(1). Reagents 1: Wittig reagent and reaction

The Wittig Reaction allows the preparation of an alkene by the reaction of an aldehyde or ketone with the ylide generated from a phosphonium salt such as triphenyl phosphonium ylide (often called a Wittig reagent).

The reaction produces an alkene and triphenylphosphine oxide Classical mechanism (2+2) Cycloaddition of the ylide to the carbonyl forms a four-membered cyclic intermediate, an oxaphosphetane. Preliminary posultated mechanisms lead first to a betaine as a zwitterionic intermediate, which would then close to the oxaphosphetane. The intermediacy of such betaines plays an important role in the Schlosser Modification. Betaines may be stabilized by lithium salts leading to side products; therefore, suitable bases in the Wittig Reaction are for example: NaH, NaOMe, NEt3.

The driving force is the formation of a very stable phosphine oxide:

Reactive ylides give rapid reaction and subsequent rapid ring opening to give the (Z)-alkene: Wittig reagents Preparation of phosphorus ylides

+ − [Ph3P CH2R]X + C4H9Li → Ph3P=CHR + LiX + C4H10

The alkylphosphonium salt is deprotonated with a strong base such as n-butyllithium

Preparation of methylenetriphenylphosphorane

Ph3PCH3Br + BuLi → Ph3PCH2 + LiBr + BuH Prepared from triphenylphosphine and methyl bromide 2: Grignard reagent and reaction The Grignard reaction is an organometallic chemical reaction in which alkyl, vinyl, or aryl- halides (Grignard reagents) add to a carbonyl group in an aldehyde or ketone. The reaction of an organic halide with magnesium is not a Grignard reaction, but provides a Grignard reagent. 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 similar to organolithium reagents because both are strong that can form new carbon–carbon bonds

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.

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: Preparation of Grignard reagent Grignard reagents form via the reaction of an alkyl or aryl halide with magnesium metal.

R−X + Mg → R−X•− + Mg•+ ………………….. step 1 The reaction is conducted by adding the organic halide to a suspension of magnesium in an etherial solvent, which provides ligands required to stabilize the organomagnesium compound R−X•− → R• + X−……………………………. Step 2 The reaction proceeds through single electron transfer R• + Mg•+ → RMg+………………………… step 3 In the Grignard formation reaction, radicals may be converted into through a second electron transfer RMg+ + X− → RMgX……………………………. Final step Limitation of Grignard reagent:

Limitation of Grignard reagents is that they do not readily react with alkyl halides via an SN2 mechanism. On the other hand, they readily participate in transmetalation reactions Solvent Most Grignard reactions are conducted in ethereal solvents, especially diethyl ether and With carbonyl compounds 3: Sarett Reagent and reaction

The highly exothermic reaction of when added to an excess of leads to the formation the CrO3 • 2 Py complex (Sarett Reagent). It oxidizes primary and secondary alcohols to aldehydes and ketones, respectively. 4: Jones reagent and reaction

The Jones Reagent is a solution of chromium trioxide in diluted sulfuric acid that can be used safely for oxidations of organic substrates in acetone. This reagent can also be prepared from dichromate and potassium dichromate. Jones Reagent is especially suitable for the oxidation of secondary alcohols to ketones and of primary alcohols to carboxylic acids and in a few cases to aldehydes Majour difference between Sarette and Jones reaction: Unlike the similar , the Sarett oxidation will not further oxidize primary alcohols to their carboxylic acid form, neither will it affect carbon-carbon double bonds. 5: Collins reagent is the complex of chromium(VI) oxide with pyridine in dichloromethane or Sarette reagent in in methylene chloride.

One advantage over the Sarett Reagent is that the addition of one equivalent chromium trioxide to a stirred solution of two equivalents of pyridine in methylene chloride allows the convenient and safe preparation of the oxidant. In addition, the use of methylene chloride as solvent and stoichiometric amounts of pyridine makes the Collins Reagent less basic than the Sarett Reagent. Thus, most acid and base-sensitive substrates can be oxidized with Collins Reagent, unlike both the Sarett and Jones Reagents.

As the Collins Reagent does not contain water (compared to the Jones Reagent) and is not as hygroscopic as is the Sarett Reagent, the oxidant is especially useful for the oxidation of primary alcohols to aldehydes where traces of water can lead to overoxidation.

It is used to selectively oxidize primary alcohols to the aldehyde, and will tolerate many other functional groups within the molecule. References

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