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Kaplan - Shechter reaction

9 January 2009 - synthetic methods

What: Kaplan–Shechter reaction. Formation of a geminal dinitro compound from the corresponding nitronate salt with silver nitrate and sodium nitrite (DOI) . Invented by Ralph B. Kaplan and Harold Shechter in 1961. Original publication described synthesis of 1,1-dinitroethane by adding a mixture of nitroethane, sodium nitrite and aqueous sodium hydroxide to a aqueous solution of silver nitrite.

Also known as: Oxidative nitration
Made obsolete: Ter Meer reaction
Why: access to new energetic materials
Modifications: Less expensive reagents than silver for this reaction are catalytic Potassium ferricyanide (ferric to ferrous) and stoichiometric re-oxidizing agent sodium persulfate (Lee et al. 1985 DOI)
See also: Organic Chemistry of Explosives Agrawal/Hodgson

The meso trick

9 November 2008 - chemistry tricks

What: The meso trick. An organic synthesis for the preparation of a enantiopure compound from a meso starting compound (desymmetrization) .
Invented by: K. Laumen and M. Schneider in 1984 (DOI). In the original publication the meso compound is the diacetate of cis-3,5-dihydroxycyclopentene. The (R)-acetate group is selectively cleaved via biocatalysis by chymotrypsin to form the hydroxyacetate. The other enantiomer can then be obtained by a sequence of Tetrahydropyranyl protection and regular hydrolysis of the (S)-acetate group. Laumen and Schneider also coined the phrase meso-trick.

Invented by: Wang et al. also in 1984 (DOI). Used pig liver esterase on the same substrate getting them 80% enantiomeric excess.
Also see: the double meso-trick (DOI)
Recently invoked in: Oseltamivir total synthesis number 4 (DOI) and number 7 (DOI, also see previous post here)

The thiol-ene reaction

3 November 2008 synthetic methods

What: The thiol-ene reaction is an organic reaction between a thiol and an alkene forming a thioether.
Discovered: Theodor Posner 1905 ( DOI)

Mechanism: In absence of initiators the reaction is an electrophilic addition obeying Markovnikov's rule very much like alcohols react to alkenes. In presence of a radical initiator such as AIBN or in a photochemical reaction the reaction type is anti-markovnikov free radical addition (Jerry March 1986). Reactions of alkenes with hydrogen sulfide also lead to thioethers through the intermediate thiol.
Use: Used extensively in polymer chemistry as crosslinking reagent and most recently in click chemistry (DOI). Key advantages: metal-free reactions and 100% atom economy.
Organic syntheses: III:458 & IV:669
Scope: Just a few examples from recent literature. Thiol-ene polymerization based on cyanuric acid and pentaerythritol was used in photolithography in a nanoelectronics application (Khire et al. DOI) citing better resistance to oxidation, lower schrinkage and more complete chemical conversion than existing network systems based on for instance acrylate monomers:

In another recent example (Jonkheijm et al. DOI) the outer layer of a sheet of silicon is converted to silicon oxide ([[chemical vapor deposition), attached is a layer of PAMAM dendrimer, to which is attached a amino caprioc acid spacer, to which is attached a cystamine linker, to which is attached (after cleavage of the disulfide bond) via thiol-ene coupling an alkene functionalized biotin molecule which can bind to streptavidin:

Copper-free Sonogashira coupling

15 august 2008 - reassessment updated 15 sept.

The Sonogashira reaction is a Csp2-Csp coupling reaction between an alkyne and a vinyl or aryl halide (Sonogashira et al 1975 DOI). In its original scope the required base was an amine and the principal catalyst based on palladium was accompanied by one based on copper. It was soon found out that this copper is not really needed and introduces a side-reaction called a Glaser coupling and therefore many copper-free Sonogashira protocols exist. Then the amine was thrown out in favor of alternative bases and in recent reports even the ligand usually attached to palladium or even palladium itself is skipped. Kind of makes you wonder what copper/amine/ligand/Pd were doing in the Sonogashira reaction in the first place, how this changes the reaction mechanism and why people have not been paying attention.

here's a reminder of what the original Sonogashira reaction looks like,

reacting iodobenzene and acetylene to diphenylacetylene with palladium as a catalyst (supported by triphenylphosphine ligands) and co-catalyst cuprous iodide.

Sonogashira was able to build on earlier work done in the same year by Cassar ( DOI) using a palladium triarylphosphine complex along with a base and Heck (of Heck reaction fame) (DOI) with a diacetatobis(triphenylphosphine)palladium(II) reaction and basically Sonogashira's claim to fame is the discovery that this type of reaction is all the more milder with cuI.

The first to throw out copper (again) were Genet in 1992 (166 citations DOI) and Alami in 1993 (249 citations DOI). Alami used tetrakis(triphenylphosphine)palladium(0) and a simple amine. he experienced a slower reaction compared to the copper catalyzed reaction and the reaction failed to work at all with several simple amines. The novel reaction was subsequently field-tested on the pharma-relevant enyne Terbinafine (DOI).

Leadbeater (2003, DOI) eliminated the need for a metal when using microwave chemistry. Other components in this protocol were humble water, sodium hydroxide and PEO but the reaction temperature of 170°C will preclude any practical applications. The report included elemental analysis on Pd and Cu (both less than 1 ppm), a rarity in this field. In the same year Leadbeater also published a copper-free reaction (DOI) looking very similar to the 1975 Heck version (both Pd(II)) and by the way not cited.

Much energy is invested in the development of new Pd catalysts. Hueze et al. employed a dendrimer based heterogeneous Pd catalyst (DOI):

and Arquez et al a ferrocene-based phosphinimine-phosphine ligand (DOI) (no rationale given for using this particular ligand other than that is was available)

Cheng et al. in 2004 DOI went from amines to inorganic base (potassium carbonate) and used a aminophosphine ligand.

In the most recent literature Sonogashira reactions are carried out with both (PPh3)2PdCl2 and an amine immobilized on a silica powder (heterogeneous!) (Sotiriou-Leventis et al. 2008, DOI) or in the inevitable ionic liquid (Hierso et al. 2007 ,DOI), (de Lima 2008, DOI). Mori et al (2008, DOI) report on a reaction with palladium on carbon (eliminating the need for a ligand), isopropanol/water and trisodium phosphate to get the job done.

The same catalyst was used by Likhar et al. with acid chloride substrates (2008, (DOI) :

How does the absence of copper affect the Sonogashira reaction mechanism. In the simple model ,copper would form a copper acetylide, palladium would form a R-Pd(II)-X intermediate by oxidative addition and a transmetallation/reductive elimination sequence would do the rest.

Soheili et al. (2003, DOI) favor a catalytic cycle based on oxidative addition, ligand exchange and Pd complexation to the alkyne, followed by deprotonation to a Pd acetylide and then product formation through reductive elimination.

This picture is further refined by Ljungdahl et al (2008, DOI) distinguishing between anionic and cationic Pd complexes

A simple mechanism offered by Gu et al. (2008, DOI) also describes oxidative addition of R-X to Pd(0) forming a R-Pd(II)-X complex followed by amine assisted ligand exchange to a R-Pd(II)-CC-R complex and reductive elimination to product.

When the starting catalyst is a Pd(II) compound, the initial Pd(0) is projected to form together with the di-alkyne, a model suffering from two flaws, the di-yne is not detected and copper-free reactions were supposed to eliminate alkyne homocouplings.

It may appear from this discussion that the copper-free Sonogashira reaction is a separate reaction set differing from the regular Sonogashira reaction and adding to the already numerous amount of coupling reactions in existence. In fact it turns out this particular reaction is really a variation of the Heck reaction and in fact it was Heck himself who set this ball rolling in 1974 and it is not surprising that the reaction is already called a Heck alkynylation in several reports ( DOI) ( DOI).

Update: In a recent Angewandte highlight Plenio (DOI) offers a different view. According to him any sp-sp3 cross-coupling reaction is in fact a Sonogashira reaction regardless of the type of metal which can be anything from Fe, Ru, Co, Ni, Cu, Ag, Au to In be it a salt or a nanoparticle. Plenio also does not believe in metal-free Sonogashiras and discredits Leadbeaters microwave chemistry: palladium can be hidden in the solvent or co-reagents, for instance in sodium carbonate in concentrations up to 50 ppb and reactions are known that run efficiently on just 0.005 mol% Pd. As to the still unsolved mechanism for Pd(II) catalysed reactions he offers a Pd(II)/Pd(IV) cycle.