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Home , Aldol condensation, Claisen condensation, Claisen rearrangement, Dibenzylideneacetone, Ylide

An Overview of the topic

There are several important name reactions in organic , called such because they either bear the names of the persons who described them or else are called by a specific name in texts and journals. Sometimes the name offers a clue about the reactants and products, but not always.

1. or Aldol Addition

The aldol is the combination of an alkene or and the carbonyl of another or ketone to form a β-hydroxy aldehyde or ketone. Aldol is a combination of the terms 'aldehyde' and '.'

2. Reaction

The aldol condensation removes the hydroxyl group formed by the aldol addition reaction in the form of in the presence of a or . The aldol condensation forms α,β-unsaturated carbonyl compounds.

3. Baeyer-Villiger Oxidation - Named Organic Reactions

The Baeyer-Villiger oxidation reaction converts a ketone into an . This reaction requires the presence of a peracid such as mCPBA or peroxyacetic acid. Hydrogen peroxide can be used in conjunction with a Lewis base to form a lactone ester.

4. Baker-Venkataraman Rearrangement

The Baker-Venkataraman rearrangement reaction converts an ortho-acylated ester into a 1,3-diketone.

5. Beckmann Rearrangement Reaction

The Beckmann rearrangement reaction converts oximes into amides. Cyclic oximes will produce lactam .

6. Benzilic Acid Rearrangement

The benzilic acid Rearrangement reaction rearranges a 1,2-diketone into an α- hydroxycarboxylic acid in the presence of a strong base. Cyclic diketones will contract the ring by the benzilic acid rearrangement. 7. Benzoin Condensation Reaction

The benzoin condensation reaction condenses a pair of aromatic into an α- hydroxyketone.

8. Friedel-Crafts Reaction

A Friedel-Crafts reaction involves the alkylation of benzene. When a is reacted with benzene using a Lewis acid (commonly an aluminum halide) as a catalyst, it will attach the alkane to the benzene ring and produce excess hydrogen halide. It is also called Friedel-Crafts alkylation of benzene.

Proper description of the named reactions

ALDOL CONDENSATION An aldol condensation is a condensation reaction in organic chemistry in which an or an ion reacts with a carbonyl compound to form a β- hydroxyaldehyde or β-hydroxyketone, followed by dehydration to give a conjugated enone.

Aldol condensations are important in , because they provide a good way to form –carbon bonds. For example, the reaction sequence features an aldol condensation; the Wieland-Miescher ketone product is an important starting material for many organic syntheses. Aldol condensations are also commonly discussed in university level organic chemistry classes as a good bond-forming reaction that demonstrates important reaction mechanisms. In its usual form, it involves the of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol" (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals.

The name aldol condensation is also commonly used, especially in , to refer to just the first (addition) stage of the process—the aldol reaction itself—as catalyzed by aldolases. However, the aldol reaction is not formally a condensation reaction because it does not involve the loss of a small .

The reaction between an aldehyde/ketone and an aromatic carbonyl compound lacking an alpha-hydrogen (cross aldol condensation) is called the Claisen-Schmidt condensation. This reaction is named after two of its pioneering investigators and J. G. Schmidt, who independently published on this topic in 1880 and 1881. An example is the synthesis of . Quantitative yields in Claisen-Schmidt reactions have been reported in the absence of solvent using as the base and plus .

Mechanism

The first part of this reaction is an aldol reaction, the second part a dehydration—an (Involves removal of a water molecule or an alcohol molecule). Dehydration may be accompanied by when an activated carboxyl group is present. The aldol addition product can be dehydrated via two mechanisms; a strong base like potassium t-butoxide, or in an enolate mechanism, or in an acid-catalyzed enol mechanism. Depending on the nature of the desired product, the aldol condensation may be carried out under two broad types of conditions: kinetic control or thermodynamic control.

Condensation Types

It is important to distinguish the aldol condensation from other addition reactions of carbonyl compounds.

 When the base is an amine and the active hydrogen compound is sufficiently activated the reaction is called a .  In a Perkin reaction the aldehyde is aromatic and the enolate generated from an anhydride.  A involves two ester compounds.  A Dieckmann condensation involves two ester groups in the same molecule and yields a cyclic molecule  A involves an aldehyde and an aliphatic .  A Robinson annulation involves a α,β-unsaturated ketone and a , which first engage in a prior to the aldol condensation.  In the , an aldehyde, formed in situ from an alcohol, self- condenses to the dimerized alcohol.  In the Japp–Maitland condensation water is removed not by an elimination reaction but by a nucleophilic displacement

DIECKMANN CONDENSATION

The Dieckmann condensation is the intramolecular of diesters with base to give β-ketoesters. It is named after the German chemist Walter Dieckmann (1869–1925). The equivalent intermolecular reaction is the Claisen condensation.

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 , while 1,7 diesters will form six-membered β-keto esters.

Animation of the

CLAISEN REARRANGEMENT

The (not to be confused with the Claisen condensation) is a powerful carbon–carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisenin 1912. The heating of an allyl vinyl will initiate a [3,3]-sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl.

The Claisen rearrangement is the first recorded example of a [3,3]-sigmatropic rearrangement.

The Claisen rearrangement is an exothermic, concerted (bond cleavage and recombination) . Woodward–Hoffmann rules show a suprafacial, stereospecific reaction pathway. The kinetics are of the first order and the whole transformation proceeds through a highly ordered cyclic transition state and is intramolecular. Crossover experiments eliminate the possibility of the rearrangement occurring via an intermolecular reaction mechanism and are consistent with an intramolecular process.

There are substantial solvent effects observed in the Claisen rearrangement, where polar solvents tend to accelerate the reaction to a greater extent. Hydrogen-bonding solvents gave the highest rate constants. For example, /water solvent mixtures give rate constants 10-fold higher than sulfolane. Trivalent organoaluminium reagents, such as trimethylaluminium, have been shown to accelerate this reaction.

The first reported Claisen rearrangement is the [3,3]-sigmatropic rearrangement of an allylphenyl 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).

If an aldehyde or occupies the ortho or para positions, the allyl side- chain displaces the group, releasing it as or , respectively.

Bellus–Claisen rearrangement

The Bellus–Claisen rearrangement is the reaction of allylic , amines, and thioethers with ketenes to give γ,δ-unsaturated esters, amides, and thioesters. This transformation was serendipitously observed by Bellus in 1979 through their synthesis of a key intermediate of an insecticide, pyrethroid. Halogen substituted ketenes (R1, R2) are often used in this reaction for their high electrophilicity. Numerous reductive methods for the removal of the resulting α-haloesters, amides and thioesters have been developed. The Bellus-Claisen offers synthetic chemists a unique opportunity for ring expansion strategies.

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. This was developed by Albert Eschenmoser in 1964. Eschenmoser-Claisen rearrangement was used as a key step in the total synthesis of morphine.

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. The E- and Z-configured silylketene acetals lead to anti and syn rearranged products, respectively. There are numerous examples of enantioselective Ireland-Claisen rearrangements found in literature to include chiral boron reagents and the use of chiral auxiliaries.

Johnson–Claisen rearrangement

The Johnson–Claisen rearrangement is the reaction of an allylic alcohol with an orthoester to a γ,δ-unsaturated ester. Weak , 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. However, microwave assisted heating in the presence of KSF-clay or propionic acid have demonstrated dramatic increases in reaction rate and yields.

Mechanism:

Photo-Claisen rearrangement

The photo-Claisen rearrangement is closely related to the photo-, that proceeds through a similar radical mechanism. Aryl ethers undergo the photo- Claisen rearrangement, while the photo-Fries rearrangement utilizes aryl esters.

Hetero-Claisens

Aza–Claisen

An iminium can serve as one of the pi-bonded moieties in the rearrangement.

By No machine-readable author provided. ~K assumed (based on copyright claims). [Public domain], via Wikimedia Commons

Chromium oxidation

Chromium can oxidize allylic alcohols to alpha-beta unsaturated on the opposite side of the unsaturated bond from the alcohol. This is via a concerted hetero- Claisen reaction, although there are mechanistic differences since the chromium has access to d- shell orbitals which allow the reaction under a less constrained set of geometries.

Chen–Mapp reaction

The Chen–Mapp reaction also known as the [3,3]-Phosphorimidate Rearrangement or Staudinger–Claisen Reaction installs a phosphite in the place of an alcohol and takes advantage of the Staudinger reduction to convert this to an . The subsequent Claisen is driven by the fact that a P=O double bond is more energetically favorable than a P=N double bond.

Overman rearrangement

The Overman rearrangement (named after Larry Overman) is a Claisen rearrangement of allylic trichloroacetimidates to allylic trichloroacetamides.

Overman rearrangement is applicable to synthesis of vicinol diamino comp from 1,2 vicinal allylic .

Zwitterionic Claisen rearrangement Unlike typical Claisen rearrangements which require heating, zwitterionic Claisen rearrangements take place at or below room temperature. The acyl ions are highly selective for Z- under mild conditions

Claisen rearrangement in nature

The enzyme (EC 5.4.99.5) catalyzes the Claisen rearrangement of chorismate ion to prephenate ion, a key intermediate in the shikimic acid pathway (the biosynthetic pathway towards the synthesis of phenylalanine and tyrosine).

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. It is named after Rainer Ludwig Claisen, who first published his work on the reaction in 1887.

Requirements

At least one of the reagents must be enolizable (have an α-proton and be able to undergo deprotonation to form the enolate anion). There are a number of different combinations of enolizable and nonenolizable carbonyl compounds that form a few different types of Claisen condensations.

The base used must not interfere with the reaction by undergoing nucleophilic substitution or addition with a carbonyl carbon. For this reason, the conjugate sodium base of the alcohol formed (e.g. if ethanol is formed) is often used, since the alkoxide is regenerated. In mixed Claisen condensations, a non- nucleophilic base such as lithium diisopropylamide, or LDA, may be used, since only one compound is enolizable. LDA is not commonly used in the classic Claisen or Dieckmann condensations due to enolization of the electrophilic ester.

The alkoxy portion of the ester must be a relatively good . Methyl and ethyl esters, which yields methoxide and ethoxide, respectively, are commonly used.

Types

 The classic Claisen condensation, a self-condensation between two molecules of a compound containing an enolizable ester.

 The mixed (or "crossed") Claisen condensation, where one enolizable ester or ketone and one nonenolizable ester are used.

 The Dieckmann condensation, where a molecule with two ester groups reacts intramolecularly, forming a cyclic β-keto ester. In this case, the ring formed must not be strained, usually a 5- or 6-membered chain or ring.

Mechanism

In the first step of the mechanism, an α-proton is removed by a strong base, resulting in the formation of an enolate anion, which is made relatively stable by the delocalization of electrons. Next, the carbonyl carbon of the (other) ester is nucleophilically attacked by the enolate anion. The alkoxy group is then eliminated (resulting in (re)generation of the alkoxide), and the alkoxide removes the newly formed doubly α-proton to form a new, highly -stabilized enolate anion. Aqueous acid (e.g. sulfuric acid or phosphoric acid) is added in the final step to neutralize the enolate and any base still present. The newly formed β-keto ester or β-diketone is then isolated. Note that the reaction requires a stoichiometric amount of base as the removal of the doubly α-proton thermodynamically drives the otherwise endergonic reaction. That is, Claisen condensation does not work with substrates having only one α-hydrogen because of the driving force effect of deprotonation of the β-keto ester in the last step.

Stobbe condensation

The Stobbe condensation is a modification specific for the diethyl ester of requiring less strong bases. An example is its reaction with benzophenone:

A reaction mechanism that explains the formation of both an ester group and a carboxylic acid group is centered on a lactone intermediate (5):

The or Wittig olefination is a chemical reaction of an aldehyde or ketone with a triphenyl ylide (often called a Wittig reagent) to give an alkene and oxide.

The Wittig reaction was discovered in 1954 by Georg Wittig, for which he was awarded the Nobel Prize in Chemistry in 1979. It is widely used in organic synthesis for the preparation of alkenes. It should not be confused with the Wittig rearrangement.

Wittig reactions are most commonly used to couple aldehydes and ketones to singly substituted ylides. With unstabilised ylides this results in almost exclusively the Z-alkene product. In order to obtain the E-alkene, stabilised ylides are used or unstabilised ylides using the Schlosser modification of the Wittig reaction can be performed.

Reaction mechanism

Classical mechanism

The steric bulk of the ylide 1 influences the stereochemical outcome of nucleophilic addition to give a predominance of the 3 (cf. Bürgi–Dunitz angle). Note that for betaine 3 both R1 and R2 as well as PPh3+ and O− are positioned anti to one another. Carbon-carbon bond rotation gives the betaine 4, which then forms the oxaphosphetane 5. Elimination gives the desired Z-alkene 7 and triphenylphosphine oxide 6. With simple Wittig reagents, the first step occurs easily with both aldehydes and ketones, and the decomposition of the betaine (to form 5) is the rate-determining step. However, with stabilised ylides (where R1 stabilises the negative charge) the first step is the slowest step, so the overall rate of alkene formation decreases and a bigger proportion of the alkene product is the E-isomer. This also explains why stabilised reagents fail to react well with sterically hindered ketones.

Mechanism

Mechanistic studies have focused on unstabilized ylides, because the intermediates can be followed by NMR spectroscopy. The existence and interconversion of the betaine (3a and 3b) is subject of ongoing research. Phosphonium ylides 1 react with carbonyl compounds 2 via a π²s/π²a [2+2] cycloaddition to directly form the oxaphosphetanes 4a and 4b. The stereochemistry of the product 5 is due to the addition of the ylide 1 to the carbonyl 2 and to the equilibration of the intermediates. Maryanoff and Reitz identified the issue about equilibration of Wittig intermediates and termed the process "stereochemical drift". For many years, the stereochemistry of the Wittig reaction, in terms of carbon-carbon bond formation, had been assumed to correspond directly with the Z/E stereochemistry of the alkene products. However, certain reactants do not follow this simple pattern. Lithium salts can also exert a profound effect on the stereochemical outcome.

Mechanisms differ for aliphatic and aromatic aldehydes and for aromatic and aliphatic phosphonium ylides. Evidence suggests that the Wittig reaction of unbranched aldehydes under lithium-salt-free conditions do not equilibrate and are therefore under kinetic reaction control. Vedejs has put forth a theory to explain the stereoselectivity of stabilized and unstabilized Wittig reactions.

Wittig reagents

Preparation of phosphorus ylides

Wittig reagents are usually prepared from a phosphonium salt, which is in turn prepared by the quaternization of triphenylphosphine with an alkyl halide. The alkylphosphonium salt is deprotonated with a strong base such as n-butyllithium:

One of the simplest ylides is methylenetriphenylphosphorane (Ph3P=CH2). It is also a precursor to more elaborate Wittig reagents. Alkylation of Ph3P=CH2 with a primary alkyl halide R−CH2−X, produces substituted phosphonium salts:

These salts can be deprotonated in the usual way to give Ph3P=CH−CH2R.

Structure of the ylide

Ball-and-stick model of Ph3P=CH2, as found in the crystal structure

The Wittig reagent may be described in the phosphorane form (the more familiar representation) or the ylide form:

The ylide form is a significant contributor, and the carbon is nucleophilic.

Reactivity

Simple phosphoranes are reactive. Most hydrolyze and oxidize readily. They are therefore prepared using air-free techniques. Phosphoranes are more air-stable when they contain an electron withdrawing group. Some examples are Ph3P=CHCO2R and Ph3P=CHPh. These ylides are sufficiently stable to be sold

commercially

From the phosphonium salts, these reagent are formed more readily, requiring only NaOH, and they are usually more air-stable. These are less reactive than simple ylides, and so they usually fail to react with ketones, necessitating the use of the Horner– Wadsworth–Emmons reaction as an alternative. They usually give rise to an E-alkene product when they react, rather than the more usual Z-alkene.

Scope and limitations

The Wittig reaction is a popular method for the synthesis of alkene from ketones and aldehydes. The Wittig reagent can generally tolerate carbonyl compounds containing several kinds of functional groups such as OH, OR, aromatic nitro and even ester groups. There can be a problem with sterically hindered ketones, where the reaction may be slow and give poor yields, particularly with stabilized ylides, and in such cases the Horner–Wadsworth–Emmons (HWE) reaction (using esters) is preferred. Another reported limitation is the often labile nature of aldehydes which can oxidize, polymerize or decompose. In a so-called Tandem Oxidation-Wittig Process the aldehyde is formed in situ by oxidation of the corresponding alcohol.

As mentioned above, the Wittig reagent itself is usually derived from a primary alkyl halide. Quaternization of triphenylphosphine with most secondary halides is inefficient. For this reason, Wittig reagents are rarely used to prepare tetrasubstituted alkenes. However the Wittig reagent can tolerate many other variants. It may contain alkenes and aromatic rings, and it is compatible with ethers and even ester groups. Even C=O and nitrile groups can be present if conjugated with the ylide- these are the stabilised ylides mentioned above. Bis-ylides (containing two P=C bonds) have also been made and used successfully.

One limitation relates to the stereochemistry of the product. With simple ylides, the product is usually mainly the Z-isomer, although a lesser amount of the E-isomer is often formed also – this is particularly true when ketones are used. If the reaction is performed in DMF in the presence of LiI or NaI, the product is almost exclusively the Z- isomer. If the E-isomer is the desired product, the Schlosser modification may be used. With stabilised ylides the product is mainly the E-isomer, and this same isomer is also usual with the HWE reaction.

Schlosser modification

The major limitation of the traditional Wittig reaction is that the reaction proceeds mainly via the erythro betaine intermediate, which leads to the Z-alkene. The erythro betaine can be converted to the threo betaine using phenyllithium at low temperature. This modification affords the E-alkene.

Allylic alcohols can be prepared by reaction of the betaine ylid with a second aldehyde. For example:

Examples

Because of its reliability and wide applicability, the Wittig reaction has become a standard tool for synthetic organic chemists.

The most popular use of the Wittig reaction is for the introduction of a methylene group using methylenetriphenylphosphorane (Ph3P=CH2). Using this reagent even a sterically hindered ketone such as camphor can be converted to its methylene derivative. In this case, the Wittig reagent is prepared in situ by deprotonation of methyltriphenylphosphonium bromide with potassium tert-butoxide. In another example, the phosphorane is produced using sodium amide as a base, and this reagent converts the aldehyde shown into alkene I in 62% yield. The reaction is performed in cold THF, and the sensitive nitro, azo and phenoxide groups are tolerated. The product can be used to incorporate a photostabiliser into a polymer, to protect the polymer from damage by UV radiation. Another example of its use is in the synthesis of leukotriene A methyl ester. The first step uses a stabilised ylide, where the carbonyl group is conjugated with the ylide preventing self condensation, although unexpectedly this gives mainly the cis product. The second Wittig reaction uses a non-stabilised Wittig reagent, and as expected this gives mainly the cis product. Note that the and ester functional groups survive intact.

Methoxymethylenetriphenylphosphine is a Wittig reagent for the homologation of aldehydes.

References

1. Schaefer, J. P.; Bloomfield, J. J. (1967). "The Dieckmann Condensation (Including the Thorpe-Ziegler Condensation)". Organic Reactions. 15: 1– 203. doi:10.1002/0471264180.or015.01. 2. Davis, B. R.; Garrett, P. J. Comp. Org. Syn. 1991, 2, 806-829. (Review) 3. Janice Gorzynski Smith (2007). Organic Chemistry (2nd ed.). pp. 932–933. ISBN 978- 0073327495. 4. "Dieckmann Condensation". Organic Chemistry Portal. 5. Wikimedia i. (Own work) [GFDL CC-BY-SA-3.0; ~K) ii. Kchemyoung (Own work) [CC BY-SA 4.0, Kchemyoung) iii. Image used with permission (Public Domain; RAN 10). iv. at the English language Wikipedia [CC-BY-SA-3.0 , GFDL, CC-BY-SA- 3.0 or CC BY-SA 3.0 , from Wikimedia Commons v. Wikimedia CommonsBy ~K (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons vi. Image used with permission (CC BY-SA 4.0; Kchemyoung) vii. By Self Made by RAN 10 (-) [CC0], via Wikimedia Commons viii. By Yikrazuul (Own work) [Public domain], via Wikimedia Commons\By The original uploader was Takometer at English Wikipedia [CC BY 2.5, via Wikimedia Commons By Howcheng at en.wikipedia [CC BY 2.5], via Wikimedia Commons

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