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Birch Reduction

The Birch Reduction offers access to substituted 1,4-cyclohexadienes.


Mechanism of the Birch Reduction

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.


Recent Literature

Fischer Esterification
Fischer-Speier Esterification

The Lewis or Brønstedt acid-catalyzed esterification of carboxylic acids with alcohols to give esters is a typical reaction in which the products and reactants are in equilibrium.

The equilibrium may be influenced by either removing one product from the reaction mixture (for example, removal of the water by azeotropic distillation or absorption by molecular sieves) or by employing an excess of one reactant.


Mechanism of the Fischer Esterification

Addition of a proton (e.g.: p-TsOH, H2SO4) or a Lewis acid leads to a more reactive electrophile. Nucleophilic attack of the alcohol gives a tetrahedral intermediate in which there are two equivalent hydroxyl groups. One of these hydroxyl groups is eliminated after a proton shift (tautomerism) to give water and the ester.

Alternative reactions employ coupling reagents such as DCC (Steglich Esterification), preformed esters (transesterification), carboxylic acid chlorides or anhydrides (see overview). These reactions avoid the production of water. Another pathway for the production of esters is the formation of a carboxylate anion, which then reacts as a nucleophile with an electrophile (similar reactions can be found here). Esters may also be produced by oxidations, namely by the Baeyer-Villiger oxidation and oxidative esterifications.


Recent Literature


Direct ester condensation from a 1:1 mixture of carboxylic acids and alcohols catalyzed by hafnium(IV) or zirconium(IV) salts
K. Ishihara, M. Nakayama, S. Ohara, H. Yamamoto, Tetrahedron, 2002, 58, 8179-8188.


Bulky Diarylammonium Arenesulfonates as Selective Esterification Catalysts
K. Ishihara, S. Nakagawa, A. Sakakura, J. Am. Chem. Soc., 2005, 127, 4168-4169.


FeCl3·6H2O as a Versatile Catalyst for the Esterification of Steroid Alcohols with Fatty Acids
K. Komura, A. Ozaki, N. Ieda, Y. Sugi, Synthesis, 2008, 3407-3410.


Direct Atom-Efficient Esterification between Carboxylic Acids and Alcohols Catalyzed by Amphoteric, Water-Tolerant TiO(acac)2
C.-T. Chen, Y. S. Munot, J. Org. Chem., 2005, 70, 8625-8627.


Scandium(III) or lanthanide(III) triflates as recyclable catalysts for the direct acetylation of alcohols with acetic acid
A. G. M. Barrett, D. C. Braddock, Chem. Commun., 1997, 351-352.


Silica Chloride: A Versatile Heterogeneous Catalyst for Esterification and Transesterification
K. V. N. S. Srinivas, I. Mahender, B. Das, Synthesis, 2003, 2390-2394.


Al2O3/MeSO3H (AMA) as a new reagent with high selective ability for monoesterification of diols
H. Sharghi, M. Hosseini Sarvari, Tetrahedron, 2003, 59, 3627-3633.

Ester Pyrolysis

Ester Pyrolysis is a syn-elimination yielding an alkene, similar to the Cope Elimination, for which ß-hydrogens are needed. The carboxylic acid corresponding to the ester is a byproduct.
The cyclic transition state can only be achieved if the steric environment is not too demanding. See Hofmann's Rule.

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. Normally, a stoichiometric amount of the Lewis acid catalyst is required, because both the substrate and the product form complexes.

The Friedel-Crafts Alkylation may give polyalkylated products, so the Friedel-Crafts Acylation is a valuable alternative. The acylated products may easily be converted to the corresponding alkanes via Clemmensen Reduction or Wolff-Kishner Reduction.


Mechanism of the Friedel-Crafts Acylation


Recent Literature


Reactions on a Solid Surface. A Simple, Economical and Efficient Friedel-Crafts Acylation Reaction over Zinc Oxide (ZnO) as a New Catalyst
M. H. Sarvari, H. Sharghi, J. Org. Chem., 2004, 69, 6953-6956.


Mild, Efficient Friedel-Crafts Acylations from Carboxylic Acids Using Cyanuric Chloride and AlCl3
C. O. Kangani, B. W. Day, Org. Lett., 2008, 10, 2645-2648.


Simple and Improved Procedure for the Regioselective Acylation of Aromatic Ethers with Carboxylic Acids on the Surface of Graphite in the Presence of Methanesulfonic Acid
M. H. Sarvari, H. Sharghi, Synthesis, 2004, 2165-2168.


Zinc Mediated Friedel-Crafts Acylation in Solvent-Free Conditions under Microwave Irradiation
M. H. Sarvari, H. Sharghi, J. Org. Chem., 2004, 69, 6953-6956.


Aluminum dodecatungstophosphate (AlPW12O40) as a non-hygroscopic Lewis acid catalyst for the efficient Friedel-Crafts acylation of aromatic compounds under solvent-less conditions
H. Firouzabadi, N. Iranpoor, F. Nowrouzi, Tetrahedron, 2004, 60, 10843-10850.


Esters as Acylating Reagent in a Friedel-Crafts Reaction: Indium Tribromide Catalyzed Acylation of Arenes Using Dimethylchlorosilane
Y. Nishimoto, S. A. Babu, M. Yasuda, A. Baba, J. Org. Chem., 2008, 73, 9465-9468.


In(III)-Mediated Chemoselective Dehydrogenative Interaction of ClMe2SiH with Carboxylic Acids: Direct Chemo- and Regioselective Friedel-Crafts Acylation of Aromatic Ethers
S. A. Babu, M. Yasuda, A. Baba, Org. Lett., 2007, 9, 405-408.

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. Since alkyl substituents activate the arene substrate, polyalkylation may occur. A valuable, two-step alternative is Friedel-Crafts Acylation followed by a carbonyl reduction.


Mechanism of the Friedel-Crafts Alkylation

Using alkenes :


Recent Literature


Dicationic Electrophiles from Olefinic Amines in Superacid
Y. Zhang, A. McElrea, G. V. Sanchez, D. Do, A. Gomez, S. L . Aguirre, R. Rendy, D. A. Klumpp, J. Org. Chem., 2003, 68, 5119-5122.


Samarium Triflate-Catalyzed Halogen-Promoted Friedel-Crafts Alkylation with Alkenes
S. Haira, B. Maji, S. Bar, Org. Lett., 2007, 9, 2783-2786.


Dramatic Enhancement of Catalytic Activity in an Ionic Liquid: Highly Practical Friedel-Crafts Alkenylation of Arenes with Alkynes Catalyzed by Metal Triflates
C. E. Song, D.-U. Jung, S. Y. Choung, E. J. Roh, S.-G. Lee, Angew. Chem. Int. Ed., 2004, 43, 6183-6185.

Grignard Reaction
Grignard Reagents

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 also used in the following important reactions: The addition of an excess of a Grignard reagent to an ester or lactone gives a tertiary alcohol in which two alkyl groups are the same, and the addition of a Grignard reagent to a nitrile produces an unsymmetrical ketone via a metalloimine intermediate. (Some more reactions are depicted below)


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.

A reduction can also take place, in which a hydride is delivered from the β-carbon of the Grignard reagent to the carbonyl carbon via a cyclic six-membered transition state.

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:


Recent Literature


Highly Enantioselective Desymmetrization of Anhydrides by Carbon Nucleophiles: Reaction of Grignard Reagents in the Presence of (-)-Sparteine
R. Shintani, G. C. Fu, Angew. Chem. Int. Ed., 2002, 41, 1057-1059.


Three-Component Coupling Reactions of Thioformamides with Organolithium and Grignard Reagents Leading to Formation of Tertiary Amines and a Thiolating Agent
M. Hatano, S. Suzuki, K. Ishihara, J. Am. Chem. Soc., 2006, 128, 9998-9999.

Hofmann's Rule

Hofmann's Rule implies that steric effects have the greatest influence on the outcome of the Hofmann or similar eliminations. The loss of the β-hydrogen occurs preferably from the most unhindered (least substituted) position [-CH3 > -CH2-R > -CH(R2)]. The product alkene with fewer substitutents will predominate.

Ester Pyrolysis also obeys this preference, and the Hofmann Rule is generally followed whenever a reaction passes through a cyclic transition state.

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 of the Brown Hydroboration

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:

Oxidation with hydrogen peroxide leads to alcohols:

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

The reactivity and selectivity of the borane reagent may be modified through the use of borane-Lewis base complexes.


Recent Literature


Hydroboration. 97. Synthesis of New Exceptional Chloroborane-Lewis Base Adducts for Hydroboration. Dioxane-Monochloroborane as a Superior Reagent for the Selective Hydroboration of Terminal Alkenes
J. V. B. Kanth, H. C. Brown, J. Org. Chem, 2001, 66, 5359-5365.


Hydroboration with Pyridine Borane at Room Temperature
J. M. Clay, E. Vedejs, J. Am. Chem. Soc., 2005, 127, 5766-5767.


Hydroboration with Pyridine Borane at Room Temperature
J. M. Clay, E. Vedejs, J. Am. Chem. Soc., 2005, 127, 5766-5767.


Sodium perborate: a mild and convenient reagent for efficiently oxidizing organoboranes
G. W. Kabalka, T. M. Shoup, N. M. Goudgaon, J. Org. Chem., 1989, 5930-5933.


Dod-S-Me and Methyl 6-Morpholinohexyl Sulfide (MMS) as New Odorless Borane Carriers
P. K. Patra, K. Nishide, K. Fuji, M. Node, Synthesis, 2004, 1003-1006.


A mild hydroboration of various 1-alkynes with pinacolborane was achieved in the presence of a catalytic amount of dicyclohexylborane at room temperature under neat conditions to afford the corresponding (E)-1-alkenylboronic acid pinacol esters in good yields.
K. Shirakawa, A. Arase, M. Hoshi, Synthesis, 2004, 1814-1820.


Highly Stereoselective Synthesis of cis-Alkenyl Pinacolboronates and Potassium cis-Alkenyltrifluoroborates via a Hydroboration/Protodeboronation Approach
G. A. Molander, N. M. Ellis, J. Org. Chem., 2008, 73, 6841-6844.


Nickel-Catalyzed 1,4-Addition of Trialkylboranes to α,β-Unsaturated Esters: Dramatic Enhancement by Addition of Methanol
K. Hirano, H. Yorimitsu, K. Oshima, Org. Lett., 2007, 9, 1541-1544.


Concise Formation of 4-Benzyl Piperidines and Related Derivatives Using a Suzuki Protocol
S. Vice, T. Bara, A. Bauer, C. A. Evans, J. Fort, H. Josien, S. McCombie, M. Miller, D. Nazzareno, A. Palani, J. Tagat,  J. Org. Chem, 2001, 66, 2487-2492.

Kolbe Electrolysis

The electrochemical oxidative decarboxylation of carboxylic acid salts that leads to radicals, which dimerize. It is best applied to the synthesis of symmetrical dimers, but in some cases can be used with a mixture of two carboxylic acids to furnish unsymmetrical dimers.

Mechanism of the Kolbe Electrolysis

Side products:

The formation of side products depends on the ease of the follow-up oxidation which leads to carbenium ions, and their subsequent rearrangement:


Recent Literature


Kolbe Carbon-Carbon Coupling Electrosynthesis Using Solid-Supported Bases
H. Kurihara, T. Fuchigami, T. Tajima, J. Org. Chem., 2008, 73, 6888-6890.

Markovnikov's Rule

Markovnikov Rule predicts the regiochemistry of HX addition to unsymmetrically substituted alkenes.

The halide component of HX bonds preferentially at the more highly substituted carbon, whereas the hydrogen prefers the carbon which already contains more hydrogens.

Anti-Markovnikov

Some reactions do not follow Markovnikov's Rule, and anti-Markovnikov products are isolated. This is a feature for example of radical induced additions of HX and of Hydroboration.


Mechanism

The proton adds first to the carbon-carbon double bond. The carbon bearing more substituents forms a more stable carbenium ion; attack of bromide ion follows in a second step:

Markovnikov

Radical reactions require an initiation step. In this example, a bromo radical is formed.

The reversal of the regiochemistry of addition is the result of the reversal of the order in which the two components add to the alkene. Radical addition leads to the formation of the more stable radical, which reacts with HBr to give product and a new bromo radical:

Anti-Markovnikov

Olefin Metathesis
Grubbs Reaction

Olefin Metathesis allows the exchange of substituents between different olefins - a transalkylidenation.

This reaction was first used in petroleum reformation for the synthesis of higher olefins (Shell higher olefin process - SHOP), with nickel catalysts under high pressure and high temperatures. Nowadays, even polyenes with MW > 250,000 are produced industrially in this way.

Synthetically useful, high-yield procedures for lab use include ring closure between terminal vinyl groups, cross metathesis - the intermolecular reaction of terminal vinyl groups - and ring opening of strained alkenes. When molecules with terminal vinyl groups are used, the equilibrium can be driven by the ready removal of the product ethene from the reaction mixture. Ring opening metathesis can employ an excess of a second alkene (for example ethene), but can also be conducted as a homo- or co-polymerization reaction. The driving force in this case is the loss of ring strain.

All of these applications have been made possible by the development of new homogeneous catalysts. Shown below are some of these catalysts, which tolerate more functional groups and are more stable and easy to handle.

The Schrock catalysts are more active and are useful in the conversion of sterically demanding substrates, while the Grubbs catalysts tolerate a wide variety of functional groups.

The second generation Grubbs catalysts are even more stable and more active than the original versions. Some of these are depicted:


K. Grela, S. Harutyunyan, A. Michrowska, Angew. Chem. Int. Ed., 2002, 114, 4038. DOI


Mechanism of Olefin Metathesis

Initiation:

Catalytic Cycle:

Chauvin Mechanism


Recent Literature


Prevention of Undesirable Isomerization during Olefin Metathesis
S. H. Hong, D. P. Sander, C. W. Lee, R. H. Grubbs, J. Am. Chem. Soc., 2005, 127, 17160-17161.


A Rapid and Simple Cleanup Procedure for Metathesis Reactions
B. R. Galan, K. P. Kalbarczyk, S. Szczepankiewicz, J. B. Keister, S. T. Diver, Org. Lett., 2007, 9, 1203-1206.


Advanced Fine-Tuning of Grubbs/Hoveyda Olefin Metathesis Catalysts: A Further Step toward an Optimum Balance between Antinomic Properties
M. Bieniek, R. Bujok, M. Cabaj, N. Lugan, G. Lavigne, D. Arlt, K. Grela, J. Am. Chem. Soc., 2006, 128, 13652-13653.


Efficient Method for the Synthesis of Chiral Pyrrolidine Derivatives via Ring-Closing Enyne Metathesis Reaction
Q. Yang, H. Alper, W.-J Xiao, Org. Lett., 2007, 9, 769-771.

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. DOI) and has been recently revisited using 17O-NMR Spectroscopy by the Berger Group (Eur. J. Org. Chem., 1998, 1625. DOI).

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 (for example the Griesbaum Coozonolysis). Some reactions can be found here: V. D.B. Bonifacio, Org. Chem. Highlights 2004, October 25. Link

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.


Recent Literature


Ozonolysis in Solvent/Water Mixtures: Direct Conversion of Alkenes to Aldehydes and Ketones
C. E. Schiaffo, P. H. Dussault, J. Org. Chem., 2008, 73, 4688-4690.


Unsymmetrical Ozonolysis of a Diels-Alder Adduct: Practical Preparation of a Key Intermediate for Heme Total Synthesis
D. F. Taber, K. Nakajima, J. Org. Chem., 2001, 70, 2515-2517.


Catalytic Asymmetric Reductive Coupling of Alkynes and Aldehydes: Enantioselective Synthesis of Allylic Alcohols and α-Hydroxy Ketones
K. M. Miller, W.-S. Huang, T. F. Jamison, J. Am. Chem. Soc., 2003, 125, 3442-3443.

Sandmeyer Reaction

The substitution of an aromatic amino group is possible via preparation of its diazonium salt and subsequent displacement with a nucleophile (Cl-, I-, CN-, RS-, HO-). Many Sandmeyer Reactions proceed under copper(I) catalysis, while the Sandmeyer-type reactions with thiols, water and potassium iodide don't require catalysis.

The Sandmeyer Reaction is a very important transformation in aromatic chemistry, because it can result in some substitution patterns that are not achievable by direct substitution.

Fluorination is possible by using the related  Schiemann Reaction.


Mechanism of the Sandmeyer Reaction


Recent Literature


Catalytic Sandmeyer Bromination
I. P. Beletskaya, A. S. Sigeev, A. S. Peregudov, P. V. Petrovskii, Synthesis, 2007, 2534-2538.


Halo- and Azidodediazoniation of Arenediazonium Tetrafluoroborates with Trimethylsilyl Halides and Trimethylsilyl Azide and Sandmeyer-Type Bromodediazoniation with Cu(I)Br in [BMIM][PF6] Ionic Liquid
A. Hubbard, T. Okazaki, K. K. Laali, J. Org. Chem., 2008, 73, 316-319.


Unusually Stable, Versatile, and Pure Arenediazonium Tosylates: Their Preparation, Structures, and Synthetic Applicability
V. D. Filimonov, M. Trusova, P. Postnikov, E. A. Krasnokutskaya, Y. M. Lee, H. Y. Hwang, H. Kim, K.-W. Chi, Org. Lett., 2008, 10, 3961-3964.


Sulfonic Acid Based Cation-Exchange Resin: A Novel Proton Source for One-Pot Diazotization-Iodination of Aromatic Amines in Water
V. D. Filimonov, N. I. Semenischeva, E. A. Krasnokutskaya, A. N. Tretyakov, H. Y. Hwang, K.-W. Chi, Synthesis, 2008, 185-187.

Saytzeff's Rule

Saytzeff Rule implies that base-induced eliminations (E2) will lead predominantly to the olefin in which the double bond is more highly substituted, i.e. that the product distribution will be controlled by thermodynamics.

The use of sterically hindered bases raises the activation energy barrier for the pathway to the product predicted by Saytzeff's Rule. Thus, a sterically hindered base will preferentially react with the least hindered protons, and the product distribution will be controlled by kinetics.

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 of the Balz-Schiemann Reaction

see Diazotisation.

The mechanism of the Balz-Schiemann reaction remains obscure. A possible pathway is shown below:


Recent Literature

Wohl-Ziegler Reaction

The bromination of allylic positions with N-bromosuccinimide (NBS) follows a radical pathway.


Mechanism of the Wohl-Ziegler Reaction

It is very important to keep the concentration of Br2 and HBr low to prevent side reactions derived from simple ionic addition with the alkene. These reagents are therefore generated in situ from NBS. The catalytically active species is Br2, which is almost always present in NBS samples (red colour).

A radical initiator (UV, AIBN) is needed for the homolytic bond cleavage of Br2 :

The allylic position is favoured for hydrogen abstraction, because the resulting radical intermediate is resonance stabilized: 

Regeneration of Br2:

Bromination:

Bromination is favored to occur at the more highly substituted position, because the corresponding intermediate radicals are better stabilized.

CCl4 is the solvent of choice, because NBS is poorly soluble and resulting succinimide is insoluble and floats at the surface. This keeps the concentration of reagents low and is a signal that the reaction is finished.

However, environmental concerns have all but eliminated the use of CCl4, and its replacement, CH2Cl2, is being restricted as well. Many other solvents are reactive toward NBS, and are thus unsuitable, but acetonitrile can be used to good effect.

 

Wolff-Kishner Reduction

The reduction of aldehydes and ketones to alkanes. Condensation of the carbonyl compound with hydrazine forms the hydrazone, and treatment with base induces the reduction of the carbon coupled with oxidation of the hydrazine to gaseous nitrogen, to yield the corresponding alkane.

The Clemmensen Reduction can effect a similar conversion under strongly acidic conditions, and is useful if the starting material is base-labile.


Mechanism of the Wolff-Kishner Reduction


Recent Literature

Wolff Rearrangement

The Wolff Rearrangement allows the generation of ketenes from α-diazoketones. Normally, these ketenes are not isolated, due to their high reactivity to form diketenes.

Wolff rearrangements that are conducted in the presence of nucleophiles generate derivatives of carboxylic acids, and in the presence of unsaturated compounds can undergo [2+2] cycloadditions (for example Staudinger Synthesis).

The formation of α-diazoketones from carboxylic acids (via the acyl chloride or an anhydride) and the subsequent Wolff Rearrangement in the presence of nucleophiles results in a one-carbon homologation of carboxylic acids. This reaction sequence, which first showed the synthetic potential of the Wolff-Rearrangement, was developed by Arndt and Eistert.


Mechanism of the Wolff Rearrangement

α-Diazoketones undergo the Wolff Rearrangement thermally in the range between room temperature and 750 °C in gas phase pyrolysis. Due to competing reactions at elevated temperatures, the photochemical and metal-catalyzed variants that feature a significantly lowered reaction temperature are often preferred (Zeller, Angew. Chem. Int. Ed., 1975, 14, 32. DOI).

Nitrogen extrusion and the 1,2-shift can occur either in a concerted manner or stepwise via a carbene intermediate:

Silver ion catalysis fails with sterically hindered substrates, pointing to the requisite formation of a substrate complex with the ion. In these cases, photochemical excitation is the method of choice.

The solvent can affect the course of the reaction. If Wolff-Rearrangements are conducted in MeOH as solvent, the occurrence of side products derived from an O-H insertion point to the intermediacy of carbenes:

The course of the reaction and the migratory preferences can depend on the conditions (thermal, photochemical, metal ion catalysis) of the reaction. Analysis of the product distribution helps to determine different degrees of concertedness or the migratory aptitude of the group that rearranges. If R is phenyl, the main product comes from the rearrangement, whereas the methyl group gives more of the insertion side product.

The reactions of 2-diazo-1,3-diones also help to determine the migratory aptitude:

In a photolysis, methyl is preferred for rearrangement, whereas under thermolysis conditions the phenyl substituent migrates preferentially. Hydrogen always exceeds the migratory aptitude of phenyl groups. The alkoxy group in aryl or alkyl 2-diazoketocarboxylates never migrates.

More detailed explanations and additional examples can be found in a recent review by Kirmse (Eur. J. Org. Chem., 2002, 2193-2256. DOI).


Recent Literature


Synthesis of Fmoc-β-Homoamino Acids by Ultrasound-Promoted Wolff Rearrangement
A. Müller, C. Vogt, N. Sewald, Synlett, 2006, 837-841.


Synthesis of β-Lactams from Diazoketones and Imines: The Use of Microwave Irradiation
M. R. Linder, J. Podlech, Org. Lett., 2001, 3, 1849-1851.

Wurtz Reaction

The Wurtz Coupling is one of the oldest organic reactions, and produces the simple dimer derived from two equivalents of alkyl halide. The intramolecular version of the reaction has also found application in the preparation of strained ring compounds:

Using two different alkyl halides will lead to an approximately statistical mixture of products. A more selective unsymmetric modification is possible if starting materials have different rates of reactivity  (see Wurtz-Fittig Reaction).


Mechanism of the Wurtz Reaction

Side products:

 

Wurtz-Fittig Reaction

This reaction allows the alkylation of aryl halides. The more reactive alkyl halide forms an organosodium first, and this reacts as a nucleophile with an aryl halide as the electrophile. Excess alkyl halide and sodium may be used if the symmetric coupled alkanes formed as a side product may be separated readily.

Yamaguchi Esterification

The Yamaguchi Esterification allows the mild synthesis of highly functionalized esters. After formation of a mixed anhydride between the Yamaguchi Reagent (2,4,6-trichlorobenzoyl chloride) and the carboxylic acid, the volatiles are removed and the reaction of the anhydride with an alcohol in presence of a stoichiometric amount of DMAP generates the desired ester.


Mechanism of the Yamaguchi Esterification

Addition of the carboxylate to the carboxylic acid chloride forms the mixed anhydride:

DMAP is an acyl transfer reagent that reacts regioselectively at the less hindered carbonyl site:

DMAP is a stronger nucleophile than the alcohol. The newly formed intermediate is less hindered, the acyl group is still polarized and DMAP is a good leaving group, all of which enable a fast reaction with the alcohol.

In reactions with aliphatic carboxylic acids, there is no need for a two step-procedure. It has been shown by SantaLucia, Jr that slight reactivity differences in this case can even lead to the formation of the symmetric aliphatic anhydrides, as shown in the following reaction pathway:

 

 


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