ORGANIC CHEMISTRY NAMING REACTION
FROM' A 'TO' B' POSTED BY ESKORGANIC NAMING REACTION
‘A’ SERIES
1. Acetoacetic Ester Synthesis
When α-keto acetic acid is treated with one mole of a base, the methylene group which is more acidic reacts with the base. And the reaction with an alkylation reagent gives alkyl products attached to methylene. When this reaction is repeated in the next step, the other hydrogen can also react to a dialkyl product. The two alkylation agents may be the same or different (R',R'').
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β-Keto esters tend to decarboxylate after hydrolysation to β-keto carboxylic acid and heating to give one or two alkyl-substituted ketones, respectively.
If two moles of a base are added in the first step, the hydrogen of the more acidic methylene group, and in the next step the hydrogen of the methyl group (ambident nucleophiles), reacts with the base. The hydrogenated methyl group is, however, more acidic than the hydrogenated methylene group. The reaction with alkylation agent in the following step gives a product substituted at methyl group. This can be synthetically used to prepare selectively ketones of different types.
2.Acetoacetic-Ester CondensationClaisen Condensation
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The Claisen Condensation between esters containing α-hydrogens, promoted by a base such as sodium ethoxide, affords β-ketoesters. The driving force is the formation of the stabilized anion of the β-keto ester. If two different esters are used, an essentially statistical mixture of all four products is generally obtained, and the preparation does not have high synthetic utility.
However, if one of the ester partners has enolizable α-hydrogens and the other does not (e.g., aromatic esters or carbonates), the mixed reaction (or crossed Claisen) can be synthetically useful. If ketones or nitriles are used as the donor in this condensation reaction, a β-diketone or a β-ketonitrile is obtained, respectively.
The use of stronger bases, e.g. sodium amide or sodium hydride instead of sodium ethoxide, often increases the yield.
Mechanism
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3.Acyloin Condensation
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The bimolecular reductive coupling of carboxylic esters by reaction with metallic sodium in an inert solvent under reflux gives an α-hydroxyketone, which is known as an acyloin. This reaction is favoured when R is an alkyl. With longer alkyl chains, higher boiling solvents can be used. The intramolecular version of this reaction has been used extensively to close rings of different sizes, e.g. .
If the reaction is carried out in the presence of a proton donor, such as alcohol, simple reduction of the ester to the alcohol takes place (Bouveault-Blanc Reduction<.
The Benzoin Condensation produces similar products, although with aromatic substituents and under different conditions.
When the acyloin condensation is carried out in the presence of chlorotrimethylsilane, the enediolate intermediate is trapped as the bis-silyl derivative. This can be isolated and subsequently is hydrolysed under acidic condition to the acyloin, which gives a better overall yield.
Mechanism
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4.Alder-Ene ReactionEne Reaction
The four-electron system including an alkene π-bond and an allylic C-H σ-bond can participate in a pericyclic reaction in which the double bond shifts and new C-H and C-C σ-bonds are formed. This allylic system reacts similarly to a diene in a Diels-Alder Reaction, while in this case the other partner is called an enophile, analogous to the dienophile in the Diels-Alder. The Alder-Ene Reaction requires higher temperatures because of the higher activation energy and stereoelectronic requirement of breaking the allylic C-H σ-bond.
The enophile can also be an aldehyde, ketone or imine, in which case β-hydroxy- or β-aminoolefins are obtained. These compounds may be unstable under the reaction conditions, so that at elevated temperature (>400°C) the reverse reaction takes place - the Retro-Ene Reaction.
While mechanistically different, the Ene reaction can produce a result similar to the Prins Reaction.
Mechanism
Also like the Diels-Alder, some Ene Reactions can be catalyzed by Lewis Acids. Lewis-Acid catalyzed Ene Reactions are not necessarily concerted (for example: Iron(III) Chloride Catalysis of the Acetal-Ene Reaction).
5.Aldol Addition Aldol Reaction
'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.
Mechanism
Under conditions of kinetic control, the mixed Aldol Addition can be used to prepare adducts that are otherwise difficult to obtain selectively. This process begins with the irreversible generation of the kinetic enolate, e.g. by employing a sterically hindered lithium amide base such as LDA (lithium diisopropylamide). With an unsymmetrically substituted ketone, such a non-nucleophilic, sterically-demanding, strong base will abstract a proton from the least hindered side. Proton transfer is avoided with lithium enolates at low temperatures in ethereal solvents, so that addition of a second carbonyl partner (ketone or aldehyde) will produce the desired aldol product.
6.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
7.Appel Reaction
The reaction of triphenylphosphine and tetrahalomethanes (CCl4, CBr4) with alcohols is a ready method to convert an alcohol to the corresponding alkyl halide under mild conditions. The yields are normally high.
This reaction is somewhat similar to the Mitsunobu Reaction, where the combination of a phosphine, a diazo compound as a coupling reagent, and a nucleophile are used to invert the stereochemistry of an alcohol or displace it.
This reaction is somewhat similar to the Mitsunobu Reaction, where the combination of a phosphine, a diazo compound as a coupling reagent, and a nucleophile are used to invert the stereochemistry of an alcohol or displace it.
Mechanism
The reaction proceeds by activation of the triphenylphosphine by reaction with the tetrahalomethane, followed by attack of the alcohol oxygen at phosphorus to generate an oxyphosphonium intermediate. The oxygen is then transformed into a leaving group, and an SN2 displacement by halide takes place, proceeding with inversion of configuration if the carbon is asymmetric.
8. Arbuzov Reaction Michaelis-Arbuzov Reaction
The reaction of a trialkyl phosphate with an alkyl halide to produce an alkyl phosphonate. The first step involves nucleophilic attack by the phosphorus on the alkyl halide, followed by the halide ion dealkylation of the resulting trialkoxyphosphonium salt.
This reaction sees extensive application in the preparation of phosphonate esters for use in the Horner-Emmons Reaction.
Mechanism
9.Arndt-Eistert Synthesis
The Arndt-Eistert Synthesis allows the formation of homologated carboxylic acids or their derivatives by reaction of the activated carboxylic acids with diazomethane and subsequent Wolff-Rearrangement of the intermediate diazoketones in the presence of nucleophiles such as water, alcohols, or amines.
Mechanism
In the first step of this one-carbon homologation, the diazomethane carbon is acylated by an acid chloride or mixed anhydride, to give an α-diazoketone. The excess diazomethane can be destroyed by addition of small amounts of acetic acid or vigorous stirring. Most α-diazoketones are stable and can be isolated and purified by column chromatography (see recent literature for specific methods). 
The key step of the Arndt-Eistert Homologation is the Wolff-Rearrangement of the diazoketones to ketenes, which can be accomplished thermally (over the range between r.t. and 750°C [Zeller, Angew. Chem. Int. Ed., 1975, 14, 32. DOI]), photochemically or by silver(I) catalysis. The reaction is conducted in the presence of nucleophiles such as water (to yield carboxylic acids), alcohols (to give alcohols) or amines (to give amides), to capture the ketene intermediate and avoid the competing formation of diketenes.
The method is widely used nowadays for the synthesis of β-amino acids. Peptides that contain β-amino acids feature a lower rate of metabolic degradation and are therefore of interest for pharmaceutical applications.
10.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
‘B’ SERIES
1.Baeyer-Villiger Oxidation
The Baeyer-Villiger Oxidation is the oxidative cleavage of a carbon-carbon bond adjacent to a carbonyl, which converts ketones to esters and cyclic ketones to lactones. The Baeyer-Villiger can be carried out with peracids, such as MCBPA, or with hydrogen peroxide and a Lewis acid.
The regiospecificity of the reaction depends on the relative migratory ability of the substituents attached to the carbonyl. Substituents which are able to stabilize a positive charge migrate more readily, so that the order of preference is: tert. alkyl > cyclohexyl > sec. alkyl > phenyl > prim. alkyl > CH3. In some cases, stereoelectronic or ring strain factors also affect the regiochemical outcome.
The reaction of aldehydes preferably gives formates, but sometimes only the liberated alcohol may be isolated due to the solvolytic instability of the product formate under the reaction conditions.
Mechanism
2.Baker-Venkataraman Rearrangement
The base-induced transfer of the ester acyl group in an o-acylated phenol ester, which leads to a 1,3-diketone. This reaction is related to the Claisen Condensation, and proceeds through the formation of an enolate, followed by intramolecular acyl transfer.
Mechanism
Mechanism
3.Balz-Schiemann Reaction
The conversion of aryl amines to aryl fluorides via diazotisation and subsequent thermal decomposition of the derived tetrafluoroborates or hexafluorophosphates. The decomposition may also be induced photochemically.
Mechanism
The mechanism of the Balz-Schiemann reaction remains obscure. A possible pathway is shown below:
4.Bamford-Stevens Reaction
Tosylhydrazones give alkenes upon treatment with strong bases. This reaction is performed in two steps, where the intermediate diazo compound may be isolated. Subsequent reaction with protic or aprotic solvents strongly influences the outcome of the reaction.
This reaction may be used to effect the overall transformation of a ketone to an alkene.
If an organolithium is used as the base, the reaction follows another mechanism without occurrence of carbenium ions and carbenes (see Shapiro Reaction).
Mechanism
Carbenium ions are formed in protic solvents:
...and carbenes in aprotic solvents:
5.Barton Decarboxylation
The radical decarboxylation of a Barton ester proceeds to the corresponding alkane after treatment with tributyltin hydride or t-butylmercaptan:
An alternative possibility is the introduction of a substituent by reaction with a suitable radical trapping agent:
Mechanism
The initiation of the Barton Decarboxylation ( Bu3Sn-H -> Bu3Sn. ) is effected with a radical initiator, and as with the Barton-McCombie Deoxygenation, the driving force for the reaction itself is the formation of the stable S-Sn bond.
In addition, Barton esters can also be cleaved photolytically or thermally:
If an excess of a suitable radical trapping agent is present in the reaction medium, substitution will occur; otherwise, radical recombination takes place to give the pyridyl sulfide:
The Barton Decarboxylation offers several options for the introduction of substituents - some examples are shown below:
6.Barton-McCombie ReactionBarton
6.Barton-McCombie ReactionBarton
Deoxygenation
A method for the deoxygenation of alcohols. The alcohol is first converted to the thiocarbonyl derivative, and is then treated with Bu3SnH. Once the radical chain has been initiated, attack on the Bu3Sn carrier by sulphur initiates a decomposition yielding the alkyl radical, for which Bu3SnH serves as hydrogen radical (H·) donor. The driving force for the reaction is the formation of the very stable S-Sn bonds.
Mechanism
Initiation:
The catalytic cycle, in which low concentration of .SnBu3 effects the reaction:
7.Barton-McCombie ReactionBarton Deoxygenation
A method for the deoxygenation of alcohols. The alcohol is first converted to the thiocarbonyl derivative, and is then treated with Bu3SnH. Once the radical chain has been initiated, attack on the Bu3Sn carrier by sulphur initiates a decomposition yielding the alkyl radical, for which Bu3SnH serves as hydrogen radical (H·) donor. The driving force for the reaction is the formation of the very stable S-Sn bonds.
Mechanism
Initiation:
The catalytic cycle, in which low concentration of .SnBu3 effects the reaction:
8.Baylis-Hillman Reaction
This coupling of an activated alkene derivative with an aldehyde is catalyzed by a tertiary amine (for example: DABCO = 1,4-Diazabicyclo[2.2.2]octane). Phosphines can also be used in this reaction, and enantioselective reactions may be carried out if the amine or phosphine catalyst is asymmetric.
Mechanism
A key step is the addition of the amine catalyst to the activated alkene to form a stabilized nucleophilic anion. This in situ-generated nucleophile then adds to the aldehyde. Subsequent elimination of the catalyst leads to the observed products.
Other activating nitrogen nucleophiles may be suitable too and DMAP and DBU are superior to DABCO in some cases:
product of the addition of DBU and methylacrylate
For aryl aldehydes under polar, nonpolar, and protic conditions, it has been determined that the rate-determining step is second-order in aldehyde and first-order in DABCO and acrylate. On the basis of this reaction rate data, Tyler McQuade recently proposed (J. Org. Chem. 2005, 70, 3980. DOI) the following mechanism involving the formation of a hemiacetal intermediate:
9.Beckmann Rearrangement
An acid-induced rearrangement of oximes to give amides.
This reaction is related to the Hofmann and Schmidt Reactions and the Curtius Rearrangement, in that an electropositive nitrogen is formed that initiates an alkyl migration.
Mechanism
Oximes generally have a high barrier to inversion, and accordingly this reaction is envisioned to proceed by protonation of the oxime hydroxyl, followed by migration of the alkyl substituent "trans" to nitrogen. The N-O bond is simultaneously cleaved with the expulsion of water, so that formation of a free nitrene is avoided.
10.Benzilic Acid Rearrangement
1,2-Diketones undergo a rearrangement in the presence of strong base to yield α-hydroxycarboxylic acids. The best yields are obtained when the subject diketones do not have enolizable protons.
The reaction of a cyclic diketone leads to an interesting ring contraction:
Ketoaldehydes do not react in the same manner, where a hydride shift is preferred (see Cannizzaro Reaction)
Mechanism
11.Benzoin Condensation
The Benzoin Condensation is a coupling reaction between two aldehydes that allows the preparation of α-hydroxyketones. The first methods were only suitable for the conversion of aromatic aldehydes.
Mechanism
Addition of the cyanide ion to create a cyanohydrin effects an umpolung of the normal carbonyl charge affinity, and the electrophilic aldehyde carbon becomes nucleophilic after deprotonation: A thiazolium salt may also be used as the catalyst in this reaction (see Stetter Reaction).
A strong base is now able to deprotonate at the former carbonyl C-atom:
A second equivalent of aldehyde reacts with this carbanion; elimination of the catalyst regenerates the carbonyl compound at the end of the reaction:
12.Bergman CyclizationBergman Cycloaromatization
The Bergman Cyclization allows the construction of substituted arenes through the thermal or photochemical cycloaromatization of enediynes in the presence of a H• donor such as 1,4-cyclohexadiene.
Mechanism
The cyclization is induced thermally or photochemically. Most cyclizations have a high activation energy barrier and therefore temperatures around 200 °C are needed for the cycloaromatization. The Bergman Cyclization forms a 1,4-benzenediyl diradical - a highly reactive species, that reacts with a H• donor to give the corresponding arenes.
The interest in the Bergman Cyclization was somewhat low, due to its limited substrate scope and the availability of alternative methods for the construction of substituted arenes. However, natural products that contain the enediyne moiety have been discovered recently, and these compounds have cytotoxic activity.
An example is calicheamicin, which is able to form the reactive diradical species even under physiological conditions. Here, the Bergman Cyclization is activated by a triggering reaction. A distinguishing property of this diradical species is that it can effect a dual-strand cleavage of DNA:
With the discovery of calicheamicin and similar natural products, interest in the Bergman Cyclization has increased. Many enediynes can now be viewed as potential anticancer drugs. Thus, the development of Bergman Cyclization precursors that can undergo cyclization at room temperature has attracted much attention. Now, most publications on this topic deal with the parameters that control the kinetics of the Bergman Cyclization.
For example, as shown by calicheamicin, cyclic enediynes have a lower activation barrier than acyclic enediynes. As suggested by Nicolaou in 1988, the distance between the acetylenic carbons that form the covalent bond influences the rate of cyclization. Another theory developed by Magnus and Snyder is based on the molecular strain between ground state and transition state; this seems to be more general, especially for strained cyclic systems. Often, as both the distance and the strain are not known, the development of suitable precursors remains difficult, as exemplified by the following enediyne, in which a slight change leads to a cycloaromatization:
In contrast to the Bergman Cyclization, the Myers-Saito Cyclization of allenyl enynes exhibits a much lower activation temperature while following a similar pathway:
Cyclic enyne allenes are also reactive. Neocarzinostatin is a bacterial antibiotic that also shows antitumor activity. Here, the occurrence of a Myers-Saito Cyclization sets the stage for the cleavage of DNA:
For synthetic purposes, organometallic reagents can be used to generate a precursor to the Bergman Cyclization in which the metal center forms a part of the cumulated unsaturated system; these cyclizations occur at relatively low temperatures, as shown in the example reported by Finn (J. Am. Chem. Soc. 1995, 117, 8045). Here the cyclization can be viewed as a Myers-Saito Cyclization that gives rise to a metal-centered radical:
For a review of natural products, chelation control of the cyclization and recent developments in catalyzed Bergman Cyclizations, please refer to the review by Basak and references cited therein (Chem. Rev. 2003, 103, 4077. DOI).
13.Biginelli Reaction
This acid-catalyzed, three-component reaction between an aldehyde, a ß-ketoester and urea constitutes a rapid and facile synthesis of dihydropyrimidones, which are interesting compounds with a potential for pharmaceutical application.
Mechanism
The first step in the mechanism is believed to be the condensation between the aldehyde and urea, with some similarities to the Mannich Condensation. The iminium intermediate generated acts as an electrophile for the nucleophilic addition of the ketoester enol, and the ketone carbonyl of the resulting adduct undergoes condensation with the urea NH2 to give the cyclized product.
14.Birch Reduction
The Birch Reduction offers access to substituted 1,4-cyclohexadienes.
Mechanism
The question of why the 1,3-diene is not formed, even though it would be more stable through conjugation, can be rationalized with a simple mnemonic. When viewed in valence bond terms, electron-electron repulsions in the radical anion will preferentially have the nonbonding electrons separated as much as possible, in a 1,4-relationship.
This question can also be answered by considering the mesomeric structures of the dienyl carbanion:
The numbers, which stand for the number of bonds, can be averaged and compared with the 1,3- and the 1,4-diene. The structure on the left is the average of all mesomers depicted above followed by 1,3 and 1,4-diene:
The difference between the dienyl carbanion and 1,3-diene in absolute numbers is 2, and between the dienyl carbanion and 1,4-diene is 4/3. The comparison with the least change in electron distribution will be preferred.
Reactions of arenes with +I- and +M-substituents lead to the products with the most highly substituted double bonds:
The effect of electron-withdrawing substituents on the Birch Reduction varies. For example, the reaction of benzoic acid leads to 2,5-cyclohexadienecarboxylic acid, which can be rationalized on the basis of the carboxylic acid stabilizing an adjacent anion:
Alkene double bonds are only reduced if they are conjugated with the arene, and occasionally isolated terminal alkenes will be reduced.
15.Blanc Reaction
This reaction, which is comparable to a Friedel-Crafts Alkylation, is useful for the preparation of chloromethylated arenes (for example, the Merrifield resin based on polystyrene) from the parent arene with formaldehyde, HCl, and ZnCl2.
Mechanism
The Lewis acid ZnCl2 effects formation of an oxonium ion which is reactive in electrophilic aromatic substitution. The intermediate zinc alkoxide reacts with the arene to form the chloromethylated product and zinc oxides:
When the concentration (or, effective concentration in the case of polymer residues) is high, the formation of side products due to a second addition are observed:
16.Bouveault-Blanc Reduction
This method is an inexpensive substitute for LAH reductions of esters in industrial production, and was the only alternative prior to the development of the metal hydride reducing agents. This dissolving metal reduction is also related to the Birch Reduction.
Mechanism
Sodium serves as single electron reducing agent and EtOH is the proton donor. If no proton donor is available, dimerization will take place, as the Acyloin Condensation.
17.Brown Hydroboration
The syn-addition of hydroboranes to alkenes occurs with predictable selectivity, wherein the boron adds preferentially to the least hindered carbon. This selectivity is enhanced if sterically demanding boranes are used.
Coupling the hydroboration with a subsequent oxidation of the new formed borane yields anti-Markovnikov alcohols. The hydroboration/oxidation sequence constitutes a powerful method for the regio- and stereoselective synthesis of alcohols.
The product boranes may also be used as starting materials for other reactions, such as Suzuki Couplings (see Recent Literature).
Mechanism
The selectivity of the first addition of borane can be relatively low:
The subsequent additions are more selective as the steric bulk increases, and anti-Markovnikov selectivity predominates in the end:
Sterically demanding boranes offer enhanced selectivity. One example of a sterically demanding borane (9-BBN) is generated by the double addition of borane to 1,5-cyclooctadiene:
9-Borabicyclo[3.3.1]nonane
9-Borabicyclo[3.3.1]nonane
The reactivity and selectivity of the borane reagent may be modified through the use of borane-Lewis base complexes.
18.Bucherer-Bergs Reaction
A multi-component reaction between a ketone, potassium cyanide and ammonium carbonate, which leads to the formation of hydantoins.
A pre-formed cyanohydrin can react with ammonium carbonate to give the same product:
Mechanism
The Bucherer-Bergs Reaction is equivalent to the Strecker Synthesis with "additional CO2". Hydantoins may be opened to yield N-carbamoylamino acids which form amino acids by treatment with acid or with a suitable enzyme:
19.Buchwald-Hartwig Cross Coupling Reaction
Palladium-catalyzed synthesis of aryl amines. Starting materials are aryl halides or pseudohalides (for example triflates) and primary or secondary amines.
The synthesis of aryl ethers and especially diaryl ethers has recently received much attention as an alternative to the Ullmann Ether Synthesis.
Newer catalysts and methods offer a broad spectrum of interesting conversions.
Mechanism
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