Oxymercuration-Demercuration of Alkenes

alkene alkoxymercuration-demercuration to give an alcohol

Reaction type: Electrophilic Addition

Summary

Overall transformation C=C to H-C-C-OH
This is an alternative method for hydrating alkenes to give alcohols
Typical reagents are mercury acetate, Hg(OAc)₂ in aqueous THF
Unfortunately, mercury compounds are generally quite toxic
Regioselectivity predicted by Markovnikov's rule (most highly substituted alcohol)
The reaction is not stereoselective
Reaction proceeds via the formation of a cyclic mercurinium ion (compare with bromination of alkenes)

The mercurinium ion is opened by the attack of water to complete the oxymercuration.
When the water attacks, it does so at the more highly substituted carbon.
Demercuration is effected by a reduction using sodium borohydride, NaBH₄
If the reaction is carried out in the presence of an alcohol rather than water, then ethers are obtained via an alkoxymercuration :

alkoxymercuration-demercuration to give an ether

The only difference here is a change in the nucleophile from H₂O to ROH

MECHANISM FOR REACTION OF ALKENES WITH Hg(OAc)₂ / H₂O
Step 1: The C=C π electrons act as the nucleophile with the electrophilic Hg and loss of an acetate ion as a leaving group, forming the mercurinium ion.
Step 2: Water functions as a nucleophile and attacks one of the carbons substituted with mercury resulting in cleavage of the C-Hg bond.
Step 3: The acetate ion functions as a base deprotonating the oxonium ion to give the alcohol. This completes the oxymercurationpart of the reaction.
Step 4:(mechanism not shown) The hydride reduces the Hg off, creating aC-H bond while breaking the C-Hg bond. This is the demercuration part of the process.

Organocatalysis

Organocatalysis uses small organic molecules predominantly composed of C, H, O, N, S and P to accelerate chemical reactions. The advantages of organocatalysts include their lack of sensitivity to moisture and oxygen, their ready availability, low cost, and low toxicity, which confers a huge direct benefit in the production of pharmaceutical intermediates when compared with (transition) metal catalysts.

In the example of the Knoevenagel Condensation, it is believed that piperidine forms a reactive iminium ion intermediate with the carbonyl compound:

Another organocatalyst is DMAP, which acts as an acyl transfer agent:

Steglich Esterification

Thiazolium salts are versatile umpolung reagents (acyl anion equivalents), for example finding application in the Stetter Reaction:

All of these organocatalysts are able to form temporary covalent bonds. Other catalysts can form H-bonds, or engage in pi-stacking and ion pair interactions (phase transfer catalysts). Catalysts may be specially designed for a specific task - for example, facilitating enantioselective conversions.

An early example of an enantioselective Stetter Reaction is shown below: :

D. Enders, K. Breuer, J. Runsink, Helv. Chim. Acta, 1996, 79, 1899-1902.

model explaining the facial selectivity

Enantioselective Michael Addition using phase transfer catalysis:

T. Ooi, D. Ohara, K. Fukumoto, K. Maruoka, Org. Lett., 2005, 7, 3195-3197.

The first enantioselective organocatalytic reactions had already been described at the beginning of the 20th century, and some astonishing, selective reactions such as the proline-catalyzed synthesis of optically active steroid partial structures by Hajos, Parrish, Eder, Sauer and Wiechert had been reported in 1971 (Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615; U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. 1971, 10, 496, DOI). However, the transition metal-based catalysts developed more recently have drawn the lion’s share of attention.

Hajos-Parrish-Eder-Sauer-Wiechert reaction (example)

The first publications from the groups of MacMillan, List, Denmark, and Jacobson paved the way in the year 1990. These reports introduced highly enantioselective transformations that rivaled the metal-catalyzed reactions in both yields and selectivity. Once this foundation was laid, mounting interest in organocatalysis was reflected in a rapid increase in publications on this topic from a growing number of research groups.

Proline-derived compounds have proven themselves to be real workhorse organocatalysts. They have been used in a variety of carbonyl compound transformations, where the catalysis is believed to involve the iminium form. These catalysts are cheap and readily accessible:

A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V. Ley, Org. Biomol. Chem., 2005, 3, 84-96.

Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M. Shoji, Angew. Chem. Int. Ed., 2006, 45, 958-961.

Kumaragurubaran, K. Juhl, W. Zhuang, A. Gogevig, K. A. Jorgensen, J. Am. Chem. Soc., 2002, 124, 6254-6255.

A general picture of recent developments: V. D. B. Bonifacio, Proline Derivatives in Organic Synthesis, Org. Chem. Highlights2007, March 25.

Books on Organocatalysis

Asymmetric Organocatalysis

Albrecht Berkessel, Harald Gröger

Hardcover, 440 Pages

First Edition, 2005

ISBN: 3-527-30517-3 - Wiley-VCH

Recent Literature

Display all abstracts

An efficient one-pot procedure allows the preparation of substituted quinolines from activated acetylenes and o-tosylamidocarbonyl compounds under base-catalyzed, mild conditions. The generation of a β-phosphonium enoate α-vinyl anion in situ is followed by Michael addition of the deprotonated tosylamides and subsequent rapid aldol cyclization. Detosylation of the dihydroquinoline intermediates occurred readily in the presence of aqueous HCl.

S. Khong, O. Kwon, J. Org. Chem., 2012, 77, 8257-8267.

A practical and highly enantioselective Michael addition of malonates to enones to yield 1,5-ketoesters with good yields and excellent enantioselectivities is catalyzed by a simple and readily available bifunctional primary amine-thiourea derived from 1,2-diaminocyclohexane. The addition of weak acids and elevated temperature improved the efficiency of the reaction. This approach is applicable in multigram scale synthesis.

K. Dudziński, A. M. Pakulska, P. Kwiatkowski, Org. Lett., 2012, 14, 4222-4225.

N-hydroxyphthalimide (NHPI) catalyzes a metal-free, aerobic oxidative cleavage of olefins. This methodology avoids the use of toxic metals or overstoichiometric amounts of traditional oxidants, showing good economical and environmental advantages. Based on the experimental observations, a plausible mechanism is proposed.

R. Lin, F. Chen, N. Jiao, Org. Lett., 2012, 14, 4158-4161.

A one-pot conversion of aldehydes to esters interfaces N-heterocyclic carbene-based organocatalysis with electro-organic synthesis to achieve direct oxidation of catalytically generated electroactive intermediates. A broad range of aldehyde and alcohol substrates has been converted. Furthermore, the anodic oxidation reactions are very clean, producing only H₂ gas as a result of cathodic reduction.

E. E. Finney, K. A. Ogawa, A. J. Boydston, J. Am. Chem. Soc., 2012, 134, 12374-12377.

Aryl iodides are efficient catalysts in an organocatalytic syn diacetoxylation of alkenes. A broad range of substrates, including electron-rich as well as electron-deficient alkenes, furnish the desired products in very good yields with high diastereoselectivity.

W. Zhong, S. Liu, J. Yang, X. Meng, Z. Li, Org. Lett., 2012, 14, 3336-3339.

Confined chiral Brønsted acids catalyze asymmetric oxidations of a broad range of sulfides to sulfoxides with hydrogen peroxide. The wide generality and high enantioselectivity of the developed method is comparable even to the best metal-based systems.

S. Liao, I. Čorić, Q. Wang, B. List, J. Am. Chem. Soc., 2012, 134, 10765-10768.

A direct reductive amination of ketones using the Hantzsch ester in the presence of S-benzyl isothiouronium chloride as a recoverable organocatalyst converts a wide range of ketones as well as aryl amines to the expected products in good yields.

Q. P. B. Nguyen, T. H. Kim, Synthesis, 2012, 1977-1982.

An organocatalytic Dakin oxidation of electron-rich arylaldehydes to phenols can be performed under mild, basic conditions using flavin catalysts. Catechols are readily prepared and the oxidation of 2-hydroxyacetophenone was achieved.

S. C. M. S. Hoassain, F. W. Foss, Jr, Org. Lett., 2012, 14, 2806-2809.

The in situ generation of α-amino aldehydes followed by reaction with dimethyloxosulfonium methylide under Corey-Chaykovsky reaction conditions gives 4-hydroxypyrazolidine derivatives in high yields with excellent enantio- and diastereoselectivities. This organocatalytic sequential method enables an efficient synthesis of anti-1,2-aminoalcohols.

B. S. Kumar, V. Venkataramasubramanian, A. Sudalai, Org. Lett., 2012, 14, 2468-2471.

Ozonolysis in the presence of pyridine directly generates ketones or aldehydes through a process that neither consumes pyridine nor generates any detectable peroxides. The reaction is hypothesized to involve nucleophile-promoted fragmentation of carbonyl oxides via formation of zwitterionic peroxyacetals.

R. Willand-Charnley, T. J. Fisher, B. M. Johnson, P. H. Dussault, Org. Lett., 2012, 14, 2242-2245.

A bifunctional organocatalyst efficiently catalyzed not only enantioselective conjugate addition of aromatic ketones to nitroolefins in good yields with excellent enantioselectivities but also enantioselective conjugate addition of acetone to nitroolefins in excellent yields with high enantioselectivities.

Z.-W. Sun, F.-Z. Peng, Z.-Q. Li, L.-W. Zhou, S.-X. Zhang, X. Li, Z.-H. Shao, J. Org. Chem., 2012, 77, 4103-4110.

Organocatalytic stereospecific dibromination of various functionalized alkenes was achieved using a simple thiourea catalyst and 1,3-dibromo 5,5-dimethylhydantoin as a stable, inexpensive halogen source at room temperature. The procedure was extended to alkynes and aromatic rings and to dichlorination reactions by using the 1,3-dichloro hydantoin derivative.

G. Hernández-Torres, B. Tan, C. F. Barbas III, Org. Lett., 2012, 14, 1858-1861.

A nitroxyl-radical-catalyzed oxidation using diisopropyl azodicarboxylate (DIAD) allows the conversion of various primary and secondary alcohols to their corresponding aldehydes and ketones without overoxidation to carboxylic acids. 1,2-Diols are oxidized to hydroxyl ketones or diketones depending on the amount of DIAD used.

M. Hayashi, M. Shibuay, Y. Iwabuchi, J. Org. Chem., 2012, 77, 3005-3009.

An enantioselective synthesis of γ-nitroesters by a one-pot asymmetric Michael addition/oxidative esterification of α,β-unsaturated aldehydes is based on an enantioselective organocatalytic nitroalkane addition followed by an N-bromosuccinimide-based oxidation. The γ-nitroesters are obtained in good yields and enantioselectivities, and the method provides an attractive entry to optically active γ-aminoesters, 2-piperidones, and 2-pyrrolidones.

K. L. Jensen, P. H. Poulsen, B. S. Donslund, F. Morana, K. A. Jørgensen, Org. Lett., 2012, 14, 1516-1519.

A simple chiral primary amine catalyses a highly efficient reaction for the synthesis of both Wieland-Miescher ketone and Hajos-Parrish ketone as well as their analogues in high enantioselectivity and excellent yields. This procedure represents one of the most efficient methods for the synthesis of these versatile chiral building blocks even in gram scale with 1 mol% catalyst loading.

P. Zhou, L. Zhang, S. Luo, J.-P. Cheng, J. Org. Chem., 2012, 77, 2526-2530.

The of silica-coated magnetic nanoparticles allowed the construction of magnetically recoverable organic hydride compounds. Magnetic nanoparticle-supported BNAH (1-benzyl-1,4-dihydronicotinamide) showed efficient activity in the catalytic reduction of α,β-epoxy ketones. After reaction, the catalyst can be separated by simple magnetic separation and can be reused.

H.-J. Xu, X. Wan, Y.-Y. Shen, S. Xu, Y.-S. Feng, Org. Lett., 2012, 14, 1210-1213.

Activation of diphenylsilane in the presence of a catalytic amount of an N-heterocyclic carbene (NHC) enables hydrosilylation of carbonyl derivatives under mild conditions. Presumably, a hypervalent silicon intermediate featuring strong Lewis acid character allows dual activation of both the carbonyl moiety and the hydride at the silicon center. Some interesting selectivities have been encountered.

Q. Zhao, D. P. Curran, M. Malacria, L. Fensterbank, J.-P. Goddard, E. Lacôte, Synlett, 2012, 433-437.

A bifunctional squaramide catalyzes a sulfa-Michael/aldol cascade reaction between 1,4-dithiane-2,5-diol and chalcones with a low catalyst loading to yield trisubstituted tetrahydrothiophenes with three contiguous stereogenic centers in a highly stereocontrolled manner.

J.-B. Ling, Y. Su, H.-L. Zhu, G.-Y. Wang, P.-F. Xu, Org. Lett., 2012, 14, 1090-1093.

A phosphinite derivative that can be easily prepared in two steps from commercially available aminoindanol is an effective catalyst for enantioselective acylation of diols. For the asymmetric desymmetrization of meso-1,2-diols, the corresponding monoester was obtained in high enantioselectivity.

H. Aida, K. Mori, Y. Yamaguchi, S. Mizuta, T. Moriyama, I. Yamamoto, T. Fujimoto, Org. Lett., 2012, 14, 812-815.

Commercially available and very inexpensive benzoic acids catalyze an efficient and simple isomerization of readily prepared allylic alcohols to yield cyclic products, unusual enyne, and dienols. The catalysts can be tuned for reactivity and substrate sensitivity.

J. A. McCubbin, S. Voth, O. V. Krokhin, J. Org. Chem., 2011, 76, 8537-8542.

Cinchona-alkaloid-thiourea-based bifunctional organocatalysts enable a straightforward asymmetric cycloetherification of ε-hydroxy-α,β-unsaturated ketones for the synthesis of tetrahydrofuran rings. This catalytic process represents a highly practical cycloetherification method that provides excellent enantioselectivities, even with low catalyst loadings at ambient temperature.

K. Asano, S. Matsubara, J. Am. Chem. Soc., 2011, 133, 16711-16713.

REACTION OF RLi or RMgX WITH AN ESTER
Step 1: The nucleophilic C in the organometallic reagent adds to the electrophilic C in the polar carbonyl group of the ester. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.
Step 2: The tetrahedral intermediate collapses and displaces the alcohol portion of the ester as a leaving group, this produces a ketone as an intermediate.
Step 3: The nucleophilic C in the organometallic reagent adds to the electrophilic C in the polar carbonyl group of the ketone. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.
Step 4: This is the work-up step, a simple acid/base reaction. Protonation of the alkoxide oxygen creates the alcohol product from the intermediate complex.

Chemistry learning with drrajatkumar(rajatkumar1069)

Thursday 12 September 2013

Thermodynamic verses kinetic stability discussion

Tuesday 10 September 2013

Lecture notes on cages clustures and ring compounds chemistry

Monday 9 September 2013

Structure determination using spectroscopic methods

General interpretation of hydrogen NMR spectrum

A manual for the general interpretation of infra red spectrum

Sunday 8 September 2013

Notes on MOEL diagrams of octahedral,tetrahedral and square planer complexes involving sigma and pi bonding

MOEL diagram for a square planer complex

MOEL diagrams for octahedral,tetragonal and square planer complexes

Reactions of RMgX and RLi with esters

Oxymercuration-demercuration of alkenes

Simmons Smith reaction,formation of cycloalkanes

Reactions of RMgX and RLi with aldehydes and ketones

Organocatalysis in synthesis

Organocatalysis

Sunday 1 September 2013

Basic concepts involved in the rearrangement of organic molecules

MECHANISM OF THE SIMMONS-SMITH REACTION
Step 1: A concerted reaction : both new C-C are formed simultaneously. Best viewed as the nucleophilic C=C causing loss of the iodide leaving group and the electrons from the nucleophilic C-Zn bond being used to form the other C-C bond.

NUCLEOPHILIC ADDITION OF RLi or RMgX TO AN ALDEHYDE
Step 1: The nucleophilic C in the organometallic reagent adds to the electrophilic C in the polar carbonyl group, electrons from theC=O move to the electronegative O creating an intermediate metal alkoxide complex.
Step 2: This is the work-up step, a simple acid/base reaction. Protonation of the alkoxide oxygen creates the alcohol product from the intermediate complex.