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Tuesday, July 31, 2012

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Heck Reaction

The palladium-catalyzed C-C coupling between aryl halides or vinyl halides and activated alkenes in the presence of a base is referred as the "Heck Reaction". Recent developments in the catalysts and reaction conditions have resulted in a much broader range of donors and acceptors being amenable to the Heck Reaction.
One of the benefits of the Heck Reaction is its outstanding trans selectivity.

Mechanism of the Heck Reaction



Henry Reaction


The Henry Reaction is a base-catalyzed C-C bond-forming reaction between nitroalkanes and aldehydes or ketones. It is similar to the Aldol Addition, and also referred to as the Nitro Aldol Reaction.
If acidic protons are available (i.e. when R = H), the products tend to eliminate water to give nitroalkenes. Therefore, only small amounts of base should be used if the isolation of the β-hydroxy nitro-compounds is desired.

Mechanism of the Henry Reaction



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Hiyama Coupling


The Hiyama Coupling is the palladium-catalyzed C-C bond formation between aryl, alkenyl, or alkyl halides or pseudohalides and organosilanes. This reaction is comparable to the Suzuki Coupling and also requires an activating agent such as fluoride ion or a base.

Mechanism of the Hiyama Coupling

Crucial for the success of the Hiyama Coupling is the polarization of the Si-C bond. Activation of the silane with base or fluoride ions (TASF, TBAF) leading to a pentavalent silicon compound is a first necessary step.

However, the reaction rate is also increased by using silanes with R” groups such as fluoro or alkoxy instead of alkyl. In fact, there are only a few successful examples of coupling reactions using trimethylsilane derivatives.
Another approach uses silacyclobutanes. These small-ring silanes offer enhanced Lewis acidity because angle strain is released when the silicon transitions from tetrahedral to pentavalent, which favors the activation.

Lewis acidity enhanced by strain release
A careful investigation of the reaction mechanism by Denmark (Org. Lett.20002, 2491. DOI) revealed that silacyclobutanes undergo rapid ring opening with TBAF • 3 H2O to afford a mixture of silanols and disiloxanes. Transmetallation occurs from a fluoride-activated disiloxane.

Both silanols and siloxanes have been synthesized independently and both underwent cross-coupling. These findings paved the way for the use of silanols as cross-coupling partners. In a specific approach - the Hiyama-Denmark Coupling - a fluoride activator is no longer needed.
Organosilanes are stable and easily prepared compounds with low toxicity. With the many improvements in the reaction conditions that have been reported, the Hiyama Coupling has become an interesting alternative to the Suzuki Coupling that offers a comparable scope of conversions. On the other hand, the broad commercial availability of boronic acids and boronates currently makes the Suzuki Coupling the more convenient choice.


Hiyama-Denmark Coupling


The Hiyama-Denmark Coupling is a modification of the Hiyama Coupling, in which the palladium-catalyzed coupling of deprotonated silanols with vinyl and aryl halides leads to cross-coupled products. In the Hiyama-Denmark coupling, fluoride is not needed as activator, so the reaction is compatible with substrates bearing silyl-protecting groups and can be performed in large-scale reactors.

Mechanism of the Hiyama-Denmark Coupling

The mechanistic proposal for the Hiyama Coupling includes oxidative addition to give a palladium(II) species, transmetalation and reductive elimination to regenerate the palladium catalyst:
 
For the Hiyama-Denmark Coupling, most of these steps are similar.
For the transmetalation to occur in the Hiyama Coupling, fluoride activation and the formation of a pentavalent silicon is essential. As the Hiyama-Denmark Coupling occurs in the presence of a base and also strongly depends on the steric and electronic properties of the silicon center, it was convenient to assume a mechanism for the transmetalation, in which a pentavalent silicon species is formed. Thus, it was first suggested that the in situ-generated silanolate forms an organopalladium complex, which is activated by a second equivalent of the silanolate prior to transmetalation.

Later, it has been shown, that the reaction is first-order in silanolate, so the transmetalation proceeds directly from an organopalladium(II) silanolate complex.

The new reaction is especially suitable for the conversion of aryl- and alkenyldimethylsilanolates, although aryldimethylsilanolates react much more slowly than alkenyl derivatives. Thus a second proof was established by the isolation and X-ray characterization of a quite stable palladium silanolate complex of an aryldimethylsilanolate. Heating to 100°C provided the biaryl product in quantitative yield in the absence of an activator.

This argued against a requirement for a pentavalent silicon species. In addition, the importance of complexation (Si-O-Pd) for this new transmetalation pathway was shown.
Since then, many protocols have been developed that allow the conversion of ester, ketone, and silyl-protected substrates. Mild bases such as KOSiMe3 allow the reversible deprotonation of alkenyl- or alkynyldimethylsilanols. Arylsilanolates need more forcing conditions, for example with Cs2CO3 in toluene at 90 °C. Here, the addition of water suppresses homocoupling of the halide. For electron-rich heterocycles, the irreversible deprotonation using NaH for the prior generation of silanolates proved to be a suitable alternative.

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Hofmann Elimination


Sometimes referred to as the Hofmann Degradation. This elimination reaction of alkyl trimethyl amines proceeds with anti-stereochemistry, and is generally suitable for producing alkenes with one or two substituents. The reaction follows the Hofmann Rule.

Mechanism of the Hofmann Elimination






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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.

Hofmann's Rule is valid for all intramolecular eliminations and for the Hofmann Elimination. Most bimolecular eliminations will follow Saytzeff's Rule.

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Hosomi-Sakurai Reaction







The Hosomi Sakurai Reaction involves the Lewis acid-promoted allylation of various electrophiles with allyltrimethysilane. Activation by Lewis acids is critical for an efficient allylation to take place.

Mechanism of the Hosomi-Sakurai Reaction



Note: Silicon stabilizes β carbocations (β effect)
Only catalytic amounts of Lewis acid are needed in some newer protocols. Note the use of allylsilyl chlorides instead of allyltrimethylsilane:

A. Fürstner, D. Voigtländer, Synthesis2000, 959-969.

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Huisgen Cycloaddition
1,3-Dipolar Cycloaddition



The Huisgen Cycloaddition is the reaction of a dipolarophile with a 1,3-dipolar compound that leads to 5-membered (hetero)cycles. Examples of dipolarophiles are alkenes and alkynes and molecules that possess related heteroatom functional groups (such as carbonyls and nitriles). 1,3-Dipolar compounds contain one or more heteroatoms and can be described as having at least one mesomeric structure that represents a charged dipole.

Examples of linear, propargyl-allenyl-type dipoles

An example of an allyl-type dipole. See: Ozonolysis

Mechanism of the Huisgen 1,3-Dipolar Cycloaddition


2 π-electrons of the dipolarophile and 4 electrons of the dipolar compound participate in a concerted, pericyclic shift. The addition is stereoconservative (suprafacial), and the reaction is therefore a [2s+4s] cycloaddition similar to the Diels-Alder Reaction. Attention: many authors still use "[2+3] cycloaddition", which counts the number of involved atoms but does not follow IUPAC recommendations (link). IUPAC recommends the use of "(2+3)" for the number of involved atoms instead.
A condition for such a reaction to take place is a certain similarity of the interacting HOMO and LUMO orbitals, depending on the relative orbital energies of both the dipolarophile and the dipole. Electron-withdrawing groups on the dipolarophile normally favour an interaction of the LUMO of the dipolarophile with the HOMO of the dipole that leads to the formation of the new bonds, whereas electron donating groups on the dipolarophile normally favour the inverse of this interaction. Diazomethane as an electron-rich dipolar compound therefore rapidly reacts with electron-poor alkenes, such as acrylates. Relative reactivity patterns may be found in the literature  (R. Huisgen, R. Grashey, J. Sauer in Chemistry of Alkenes, Interscience, New York, 1964, 806-877.).

The regioselectivity of the reaction depends on electronic and steric effects and is somewhat predictable. For example, the addition of alkynes to azides, which is an interesting reaction for the generation of 1,2,3-triazole libraries by the simple reaction of two molecules ("click chemistry"), leads to regioisomers:

V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed.200241, 2596-2599.
The reaction has been modified to a more regioselective, copper-catalyzed stepwise process by the Sharpless group, which is no longer a classic Huisgen Cycloaddition (for a discussion of the nonconcerted mechanism see: click chemistry) . Another approach prefers the use of a directing electron withdrawing group, which is removable later:

D. Amantini, F. Fringuelli, O. Piermatti, F. Pizzo, E. Zunino, L. Vaccaro, J. Org. Chem. 200570, 6526-6529.
In summary, the 1,3-dipolar cycloaddition allows the production of various 5-membered heterocycles. Many reactions can be performed with high regioselectivity and even enantioselective transformations of prochiral substrates have been published. Some interesting examples may be found in the recent literature.




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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.

name reaction h 1


Haloform Reaction

This reaction has been used in qualitative analysis to indicate the presence of a methyl ketone. The product iodoform is yellow and has a characteristic odour. The reaction has some synthetic utility in the oxidative demethylation of methyl ketones if the other substituent on the carbonyl groups bears no enolizable α-protons.

Mechanism of the Haloform Reaction

The reaction readily proceeds to completion because of the acidifying effect of the halogen substituents.

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Hantzsch Dihydropyridine (Pyridine) Synthesis


This reaction allows the preparation of dihydropyridine derivatives by condensation of an aldehyde with two equivalents of a β-ketoester in the presence of ammonia. Subsequent oxidation (or dehydrogenation) gives pyridine-3,5-dicarboxylates, which may also be decarboxylated to yield the corresponding pyridines.


Mechanism of the Hantzsch Dihydropyridine Synthesis

The reaction can be visualized as proceeding through a Knoevenagel Condensation product as a key intermediate:

A second key intermediate is an ester enamine, which is produced by condensation of the second equivalent of the β-ketoester with ammonia:

Further condensation between these two fragments gives the dihydropyridine derivative:



Hell-Volhard-Zelinsky Reaction


Treatment with bromine and a catalytic amount of phosphorus leads to the selective α-bromination of carboxylic acids.

Mechanism of the Hell-Volhard-Zelinsky Reaction

Phosphorus reacts with bromine to give phosphorus tribromide, and in the first step this converts the carboxylic acid into an acyl bromide.

An acyl bromide can readily exist in the enol form, and this tautomer is rapidly brominated at the α-carbon. The monobrominated compound is much less nucleophilic, so the reaction stops at this stage. This acyl intermediate compound can undergo bromide exchange with unreacted carboxylic acid via the anhydride, which allows the catalytic cycle to continue until the conversion is complete.





Glaser Coupling
Hay Coupling


The Glaser Coupling is a synthesis of symmetric or cyclic bisacetylenes via a coupling reaction of terminal alkynes. Mechanistically, the reaction is similar to the Eglinton Reaction; the difference being the use of catalytic copper(I), which is reoxidized in the catalytic cycle by oxygen in the reaction medium.
The related Hay Coupling has several advantages as compared with the Glaser Coupling. The copper-TMEDA complex used is soluble in a wider range of solvents, so that the reaction is more versatile.

A valuable alternative is the Cadiot-Chodkiewicz Coupling which allows the preparation of asymmetric bisacetylenes.