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III Semester M Sc – Organic Reactions
UNIT 2: MODERN SYNTHETIC METHODS AND REAGENTS (18 HRS)
Baylis-Hillman Reaction
The Baylis–Hillman reaction is an organic reaction of an aldehyde and an α,β-unsaturated
electron-withdrawing group catalyzed by DABCO (1,4-diazabicyclo[2.2.2]octane) to give an
allylic alcohol. This reaction is also known as the Morita–Baylis–Hillman reaction or MBH
reaction. It is named for the Japanese chemist Ken-ichi Morita, the British chemist Anthony B.
Baylis and the German chemist Melville E. D. Hillman. The Baylis–Hillman reaction, in the
present day version, is an atom-economic carbon-carbon bond formation reaction.
In addition to DABCO, additional nucleophilic amines such as DMAP(4Dimethylaminopyridine) and DBU(1,8-Diazabicycloundec-7-ene) as well as phosphines have
been found to successfully catalyze this reaction.
Reaction mechanism
The nucleophilic addition of DABCO 2 onto the α,β-unsaturated ketone 1 gives a zwitterionic
intermediate 3, which will add to the electrophilic aldehyde producing the keto-alcohol 4.
Elimination of the DABCO gives the desired allylic alcohol 5.
A simple relationship exists between pKa of the base (as its conjugate acids) and the reaction rate
with quinuclidine even more effective than DABCO. Protic additives like methanol,
triethanolamine, formamide, and water also accelerate the reaction.
Scope
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III Semester M Sc – Organic Reactions
The MBH reaction in general is any reaction of electron deficient alkenes and sp2 hybridized
carbon electrophiles such as aldehydes, ketones and aldimines catalyzed by a nucleophile. Under
special reaction conditions the reaction is also found to extend to alkyl halides as the
electrophilic reagent.
The Baylis–Hillman adducts and their derivatives have been extensively utilized for the
generation of heterocycles and other cyclic frameworks.
Limitations
The MBH reaction of phenyl vinyl ketone with benzaldehyde and DABCO in DMF is not
limited to the monoadduct because the MBH adduct reacts with a second molecule of phenyl
vinyl ketone in a nucleophilic conjugate addition.
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.
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III Semester M Sc – Organic Reactions
Henry Reaction
The Henry Reaction (also referred to as the nitro-aldol reaction) is a classic carbon–carbon
bond formation reaction in organic chemistry. Discovered in 1895 by L. Henry, it is the
combination of a nitroalkane and an aldehyde or ketone in the presence of a base to form β-Nitro
alcohols
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 βhydroxy nitro-compounds is desired.
Mechanism of the Henry Reaction
The Henry reaction begins with the deprotonation of the nitroalkane on the α-carbon position
forming a resonance stabilized anion. This is followed by alkylation of the nitroalkane with the
carbonyl containing substrate to form a diastereomeric β-nitro alkoxide. The protonation of the
alkoxide by the previously protonated base will yield the respective β-nitro alcohol as product.
The Henry reaction is a useful technique in the area organic chemistry due to the synthetic utility
of its corresponding products, as they can be easily converted to other useful synthetic
intermediates. These conversions include subsequent dehydration to yield nitroalkenes, oxidation
of the secondary alcohol to yield α-nitro ketones, or reduction of the nitro group to yield β-amino
alcohols.
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III Semester M Sc – Organic Reactions
Due to a number of factors, including the reversibility of the reaction, as well as the tendency for
easy epimerization of the nitro-substituted carbon atom, the Henry Reaction will typically
produce a mixture of enantiomers or diastereomers. It is for this reason that explanations for
stereoselectivity remain scarce without some modification. In recent years, research focus has
shifted toward modifications of the Henry Reaction to overcome this synthetic challenge.
One of the most frequently employed ways to induce enantio- or diastereoselectivity in the
Henry Reaction has been through the use of chiral metal catalysts in which the nitro group and
carbonyl oxygen coordinate to a metal that is bound to a chiral organic molecule. Some examples
of metals that have been used include Zn, Co, Cu, Mg, and Cr. One of the many features of the
Henry Reaction that makes it synthetically attractive is that it utilizes only a catalytic amount of
base to drive the reaction.
Limitations
One of the main drawbacks of the Henry Reaction is the potential for side reactions throughout
the course of the reaction. Aside from the reversibility of the reaction (Retro-Henry) which could
prevent the reaction from proceeding, the β-nitro alcohol has the potential to undergo
dehydration, and for sterically hindered substrates it is possible that a base catalyzed selfcondensation (Cannizaro reaction) could occur.
Industrial Application- An enantioselective aldol addition product can be obtained in
asymmetric synthesis by reaction of benzaldehyde with nitromethane and the a catalyst system
consisting of a zinc triflate salt / the base diisopropylethylamine (DIPEA) and as chiral ligand is
the N-methyl derivative of (+)-ephedrine (NME).
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III Semester M Sc – Organic Reactions
Nef Reaction
The conversion of nitro compounds into carbonyls is known as the Nef Reaction. Various
methodologies have been developed, but the most important is the standard procedure: a
preformed nitronate salt is poured into strong aqueous acid (pH < 1).
Mechanism
Nitroalkanes are relatively strong carbon acids, and deprotonation leads to the nitronate salt. The
hydrolysis of this intermediate must take place in strong acid, to prevent the formation of side
products such as oximes or hydroxynitroso compounds:
The procedure using the commercial reagent Oxone is mechanistically interesting:
The composition of the oxidizing agent Oxone is 2KHSO5.KHSO4.K2SO4. The active component
potassium monopersulfate (KHSO5, potassium peroxomonosulfate) is a salt from the Caro´s acid
H2SO5
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III Semester M Sc – Organic Reactions
The reductive method leads to oximes, which may be hydrolyzed to the corresponding carbonyl
compound. Ti(III) serves to reduce the N-O bond, and titanium's strong affinity towards oxygen
facilitates the hydrolysis to complete the conversion:
Kulinkovich Reaction (Cyclopropanation)
The Kulinkovich Reaction allows the preparation of cyclopropanol derivatives by the reaction of
Grignard reagents (ethyl or higher) with esters in the presence of titanium(IV) isopropoxide as
catalyst.
Mechanism
If ethylmagnesium bromide is used, the formation of ethane and a trace of ethene can be
observed. Two equivalents of the Grignard reagent react with titanium(IV) isopropoxide to give
a thermally unstable diethyltitanium compound, which rapidly undergoes β-hydride elimination
with the loss of ethane to yield the substituted titanacyclopropane:
The titanacyclopropane reacts with the ester as a 1,2-dicarbanion equivalent to produce a
cyclopropanol after a 2-fold alkylation:
Titanium(II) is reoxidized to titanium(IV) over the course of this addition process. The last
intermediate in the sequence can be recognized as a Ti(OR'')4 species, which can undergo
reaction with EtMgBr similar to Ti(OiPr)4. Thus, titanium(IV) isopropoxide can be used in
catalytic amounts:
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III Semester M Sc – Organic Reactions
The production of ethene has been attributed to a side reaction of the titanacyclopropane with
additional titanium(IV) isopropoxide to afford 2 equivalents of titanium(III) isopropoxide
Hosomi-Sakurai Reaction
The Hosomi Sakurai Reaction involves the Lewis acid-promoted allylation of various
electrophiles with allyltrimethylsilane. Activation by Lewis acids is critical for an efficient
allylation to take place.
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III Semester M Sc – Organic Reactions
Mechanism
Only catalytic amounts of Lewis acid are needed in some newer protocols.
Tishchenko Reaction
The Tishchenko Reaction is a disproportionation reaction disproportionation of an aldehyde
lacking a hydrogen atom in the alpha position in the presence of an alkoxide that allows the
preparation of esters from two equivalents of an aldehyde.
Benzaldehyde reacts with sodium benzyloxide (generated from sodium and benzyl alcohol) to
benzyl benzoate.
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III Semester M Sc – Organic Reactions
Paraformaldehyde reacts with boric acid to methyl formate. The key step in the reaction
mechanism for this reaction is a 1,3-hydride shift in the hemiacetal intermediate formed from
two successive nucleophilic addition reactions, the first one from the catalyst. The hydride shift
regenerates the alkoxide catalyst.
Mechanism
The aluminium alkoxide acts as a Lewis acid to coordinate with one molecule of the aldehyde,
and to facilitate the addition of a second equivalent of aldehyde, generating a hemiacetal
intermediate:
This species undergoes an intramolecular 1,3-hydride shift that results in the production of the
aluminium-coordinated ester.
Side reactions can be minimised, if the reaction is conducted at low temperatures and low
catalyst loadings.
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III Semester M Sc – Organic Reactions
In the related Cannizzaro reaction the base is sodium hydroxide and then the oxidation product is
a carboxylic acid and the reduction product is an alcohol.
Ugi Reaction
The Ugi four-component condensation (U-4CC) between an aldehyde, an amine, a carboxylic
acid and an isocyanide allows the rapid preparation of α-aminoacyl amide derivatives. The Ugi
Reaction products can exemplify a wide variety of substitution patterns, and constitute
peptidomimetics that have potential pharmaceutical applications. This reaction is thus very
important for generating compound libraries for screening purposes.
Mechanism
The mechanism is believed to involve a prior formation of an imine by condensation of the
amine with the aldehyde, followed by addition of the carboxylic acid oxygen and the imino
carbon across the isocyanide carbon; the resulting acylated isoamide rearranges by acyl transfer
to generate the final product.
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III Semester M Sc – Organic Reactions
Brook Rearrangement
The [1,2]-Brook Rearrangement of α-silyl carbinols is an intramolecular 1,2-anionic
migration of a silyl group from carbon to oxygen in the presence of a catalytic amount of a base
such as Et2NH, NaH or NaOH. The migratory aptitude is general over a range of homologues,
and [1,n]-carbon to oxygen migrations are commonly referred to as Brook Rearrangements.
Mechanism
The mechanism includes the formation of a cyclic pentavalent silicon species
immediately following the deprotonation. Subsequent ring opening and irreversible, fast
protonation of the carbanion by the starting alcohol or the conjugate base leads to the
corresponding silyl ether:
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III Semester M Sc – Organic Reactions
The greater strength of the oxygen-silicon bond compared to the carbon-silicon bond provides
the driving force for the conversion of silyl carbinols to the corresponding silyl ethers. An
electron-withdrawing R group facilitates the kinetics of the carbanion formation.
In the presence of a strong base in stoichiometric amounts, the equilibrium between alkoxide and
carbanion is relative to the stabilities of the corresponding anionic species:
Here, the presence of an electron withdrawing group R shifts the equilibrium to the right,
whereas counter ions that form strong ion pairs with oxygen such as lithium favor oxygen to
carbon silyl migration (retro-Brook Rearrangement). Destabilization of the alkoxides using polar
solvents such as THF also shifts the equilibrium towards the silyl ethers.
The use of a stoichiometric amount of base and the control of the equilibrium enables tandem
strategies to introduce electrophiles.
Tebbe Olefination
The Tebbe Reagent is a metal carbenoid prepared from the dimetallomethylene species derived
by the reaction of trimethyl aluminium with titanocene dichloride; this reagent exhibits carbenoid
behaviour after the addition of a catalytic amount of pyridine.
The Tebbe Reagent reacts with various carbonyl partners to give the product of methylenation.
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III Semester M Sc – Organic Reactions
Aldehydes to alkenes
Ketones to alkenes
Esters to enol ethers
Amides to enamines
Mechanism
Noyori asymmetric hydrogenation
It is a chemical reaction for the enantioselective hydrogenation of ketone, aldehydes, and
imines. This reaction exploits using chiral ruthenium catalysts introduced by Ryoji Noyori. He
shared half of the Nobel Prize in Chemistry in 2001 with William S. Knowles for the study of the
asymmetric hydrogenation.
BINAP-Ru catalyst is used for the asymmetric hydrogenation of functionalized ketones
and BINAP/diamine-Ru catalyst is used for the asymmetric hydrogenation of simple ketones.
These hydrogenations are used in the production of several drugs, such as the antibacterial
levofloxin, the antibiotic carbapenem, and the antipsychotic agent BMS181100.
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BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) is an organophosphorus
compound. This chiral ligand is widely used in asymmetric synthesis. It consists of a pair of 2diphenylphosphinonaphthyl groups linked at the 1 and 1´ positions.
Even though the BINAP-Ru dihalide catalyst could reduce functionalized ketones, the
hydrogenation of simple ketones has remained a challenge. In 1995, Noyori discovered that the
RuCl2 (diphosphane)2 (diamine)2 complex can catalyze the hydrogenation of simple ketones.
This system also had chemoselectivity on C=O bond over the C=C bond.
The
diastereoselectivity and the enantioselectivity could be achieved at the same time using chiral
BINAP ligand.
Mechanism
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III Semester M Sc – Organic Reactions
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". One of the benefits of the
Heck Reaction is its outstanding trans selectivity.
Mechanism
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III Semester M Sc – Organic Reactions
Stille Coupling
The Stille Coupling is a versatile C-C bond forming reaction between stannanes and halides or
pseudohalides, with very few limitations on the R-groups. The main drawback is the toxicity of
the tin compounds used, and their low polarity, which makes them poorly soluble in water.
Stannanes are stable, but boronic acids and their derivatives undergo much the same chemistry in
what is known as the Suzuki Coupling. Improvements in the Suzuki Coupling may soon lead to
the same versatility without the drawbacks of using tin compounds.
Convenient electrophiles and stannanes:
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III Semester M Sc – Organic Reactions
Mechanism
Suzuki Coupling
It is the palladium-catalysed cross coupling between organoboronic acid and halides. Recent
catalyst and methods have broadened the possible applications enormously, so that the scope of
the reaction partners is not restricted to aryls, but includes alkyls, alkenyls and alkynyls.
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III Semester M Sc – Organic Reactions
Potassium trifluoroborates and organoboranes or boronate esters may be used in place of boronic
acids. Some pseudohalides (for example triflates) may also be used as coupling partners.
Mechanism
One difference between the Suzuki mechanism and that of the Stille Coupling is that the boronic
acid must be activated, for example with base. This activation of the boron atom enhances the
polarisation of the organic ligand, and facilitates transmetallation. If starting materials are
substituted with base labile groups (for example esters), powdered KF effects this activation
while leaving base labile groups unaffected.
Due to the stability, ease of preparation and low toxicity of the boronic acid compounds, there is
currently widespread interest in applications of the Suzuki Coupling, with new developments and
refinements being reported constantly.
Negishi Coupling
The Negishi Coupling, published in 1977, was the first reaction that allowed the preparation of
unsymmetrical biaryls in good yields. The versatile nickel- or palladium-catalyzed coupling of
organozinc compounds with various halides (aryl, vinyl, benzyl, or allyl) has broad scope, and is
not restricted to the formation of biaryls.
Mechanism
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III Semester M Sc – Organic Reactions
Sonogashira Coupling
This coupling of terminal alkynes with aryl or vinyl halides is performed with a palladium
catalyst, a copper(I) co catalyst, and an amine base. Typically, the reaction requires anhydrous
and anaerobic conditions, but newer procedures have been developed where these restrictions are
not important.
Mechanism
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III Semester M Sc – Organic Reactions
Nozaki-Hiyama Coupling
Nozaki-Hiyama-Kishi Reaction
This coupling between halides and aldehydes is a chromium-induced redox reaction. A key
advantage is the high chemoselectivity toward aldehydes. A disadvantage is the use of excess
toxic chromium salts. Newer methods allow the use of catalytic amounts chromium(II), which is
regenerated by reduction with manganese or via electrochemical reduction.
Mechanism
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III Semester M Sc – Organic Reactions
Catalyzed Reaction:
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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III Semester M Sc – Organic Reactions
Ullmann Reaction
There are two different transformations referred as the Ullmann Reaction. The "classic" Ullmann
Reaction is the synthesis of symmetric biaryls via copper-catalyzed coupling. The "Ullmanntype" Reactions include copper-catalyzed Nucleophilic Aromatic Substitution between various
nucleophiles (e.g. substituted phenoxides) with aryl halides. The most common of these is the
Ullmann Ether Synthesis.
Mechanism
Biaryls are available through coupling of the aryl halide with an excess of copper at elevated
temperatures (200 °C). The active species is a copper(I)-compound which undergoes oxidative
addition with the second equivalent of halide, followed by reductive elimination and the
formation of the aryl-aryl carbon bond.
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III Semester M Sc – Organic Reactions
The organocopper intermediate can be generated at a more moderate 70 °C using a novel
thiophenecarboxylate reagent. The reaction otherwise follows the same reaction path as above.
Another possibility is the use of Cu(I) for the oxidative coupling of aryllithium compounds at
low temperatures. This method can also be used to generate asymmetric biaryls, after addition of
the appropriate halide.
Ullmann-type reactions proceed through a catalytic cycle, and in one mechanism the copper is
postulated to undergo oxidation to Cu(III).
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III Semester M Sc – Organic Reactions
Glaser Coupling and Hay Coupling
The Glaser Coupling is a synthesis of symmetric or cyclic bisacetylenes via a coupling reaction
of terminal alkynes.
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.
Wohl-Ziegler Reaction
The bromination of allylic positions with N-bromosuccinimide (NBS) follows a radical pathway.
Mechanism
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 :
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III Semester M Sc – Organic Reactions
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.
NBS
N-Bromosuccinimide or NBS is a chemical reagent used in radical substitution and electrophilic
addition reactions in organic chemistry. NBS can be a convenient source of cationic bromine.
Preparation
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III Semester M Sc – Organic Reactions
NBS is synthesized in the laboratory by adding sodium hydroxide and bromine to an ice-water
solution of succinimide. The NBS product precipitates out and can be collected by filtration.
Crude NBS gives better yield in the Wohl-Ziegler reaction. Impure NBS can be purified by
recrystallization from 90–95°C water.
Reactions
1. Addition to alkenes
NBS will react with alkenes 1 in aqueous solvents to give bromohydrins 2. The preferred
conditions are the portion wise addition of NBS to a solution of the alkene in 50% aqueous
DMSO, DME, THF, or tert-butanol at 0 °C. Formation of a bromonium ion and immediate
attack by water gives strong Markovnikov addition and anti stereochemical selectivities.
Side reactions include the formation of α-bromo-ketones and dibromo compounds. These can be
minimized by the use of freshly recrystallized NBS.
With the addition of nucleophiles, instead of water, various bifunctional alkanes can be
synthesized.
2. Allylic and benzylic bromination
Standard conditions for using NBS in allylic and/or benzylic bromination involves refluxing a
solution of NBS in anhydrous CCl4 with a radical initiator—usually azo-bis-isobutyronitrile
(AIBN) or benzoyl peroxide—, irradiation, or both to effect radical initiation. The allylic and
benzylic radical intermediates formed during this reaction are more stable than other carbon
radicals and the major products are allylic and benzylic bromides. This is also called the WohlZiegler reaction.
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The carbon tetrachloride must be maintained anhydrous throughout the reaction, as the presence
of water may likely hydrolyze the desired product. Barium carbonate is often added to maintain
anhydrous and acid-free conditions.
3. Bromination of carbonyl derivatives
NBS can α-brominate carbonyl derivatives via either a radical pathway (as above) or via acidcatalysis. For example, hexanoyl chloride 1 can be brominated in the alpha-position by NBS
using acid catalysis.
The reaction of enolates, enol ethers, or enol acetates with NBS is the preferred method of αbromination as it is high-yielding with few side-products.
4. Bromination of aromatic derivatives
Electron-rich aromatic compounds, such as phenols, anilines, and various aromatic heterocycles,
can be brominated using NBS. Using DMF as the solvent gives high levels of para-selectivity.
5. Hofmann rearrangement
NBS, in the presence of a strong base, such as DBU, reacts with primary amides to produce a
carbamate via the Hofmann rearrangement.
6. Selective oxidation of alcohols
We can selectively oxidize secondary alcohols in the presence of primary alcohols using NBS in
aqueous dimethoxyethane (DME).
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DDQ
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (or DDQ) is the chemical reagent with formula
C8Cl2N2O2. This oxidant is useful for the dehydrogenation of alcohols, phenols, and steroid
ketones in organic chemistry. DDQ decomposes in water, but is stable in aqueous mineral acid.
Preparation
Synthesis of DDQ involves cyanation and chlorination of 1,4-benzoquinone. Thiele and Günther
first reported a 6-step preparation in 1906. The substance did not receive interest until its
potential as a dehydrogenation agent was discovered. A single-step chlorination from 2,3dicyanohydroquinone was reported in 1965.
Stability
DDQ can react with water and give off hydrogen cyanide (HCN), which is highly toxic. Storage
should be in dry area. A low-temperature and weakly acidic environment increases the stability
of DDQ.
Uses
It is used as a reagent in organic chemistry, a mild oxidizing agent as well as a radical receptor.
Reactions
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1.Dehydrogenation
2.Aromatization
3.Oxidative Coupling
DCC
N,N'-Dicyclohexylcarbodiimide is an organic compound with the chemical formula C13H22N2
whose primary use is to couple amino acids during artificial peptide synthesis. Under standard
conditions, it exists in the form of white crystals with a heavy, sweet odor. The low melting point
of this material allows it to be melted for easy handling. It is highly soluble in dichloromethane,
tetrahydrofuran, acetonitrile and dimethylformamide, but insoluble in water. The compound is
often abbreviated DCC.
Structure and spectroscopy
The C-N=C=N-C core of carbodiimides (N=C=N) is linear, being related to the structure of
allene. Three principal resonance structures describe carbodiimides:
RN=C=NR ↔ RN+≡C-N-R ↔ RN--C≡N+R
The N=C=N moiety gives characteristic IR spectroscopic signature at 2117 cm−1. The 15N NMR
spectrum shows a characteristic shift of 275.0 ppm upfield of nitric acid and the 13C NMR
spectrum features a peak at about 139 ppm downfield from TMS.
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DCC has also been prepared from dicyclohexylurea using a phase transfer catalyst by Jaszay et
al. The disubstituted urea, arenesulfonyl chloride, and potassium carbonate react in toluene in the
presence of benzyl triethylammonium chloride to give DCC in 50% yield.
DCC is a dehydrating agent for the preparation of amides, ketones, nitriles. In these reactions,
DCC hydrates to form dicyclohexylurea (DCU), a compound that is insoluble in water. DCC can
also be used to invert secondary alcohols.
Secondary alcohols can be stereochemically inverted by formation of a formyl ester followed by
saponification. The secondary alcohol is mixed directly with DCC, formic acid, and a strong
base such as sodium methoxide.
Gilman reagent
A Gilman reagent is a lithium and copper (diorganocopper) reagent compound, R2CuLi, where
R is an organic radical. These are useful because they react with organic chlorides, bromides, and
iodides to replace the halide group with an R group. This is extremely useful in creating larger
molecules from smaller ones.
Generalized chemical reaction showing Gilman reagent reacting with organic halide to form products
and showing Cu(III) reaction intermediate
These reagents were discovered by Henry Gilman. Lithium dimethylcopper (CH3)2CuLi can be
prepared by adding copper(I) iodide to methyllithium in tetrahydrofuran at −78 °C. In the
reaction depicted below, the Gilman reagent is a methylating reagent reacting with an alkyne in a
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conjugate addition, and the negative charge is trapped in a nucleophilic acyl substitution with the
ester group forming a cyclic enone.
Gilman reagents have complicated structures in crystalline form and in solution. Lithium
dimethylcuprate is a dimer in diethyl ether forming an 8-membered ring with two lithium atoms
coordinating between two methyl groups. Similarly, lithium diphenylcuprate forms a dimeric
etherate, [{Li(OEt2)}(CuPh2)]2, in the solid state.
If the Li+ ions are rendered inert by complexation with the crown ether 12-crown-4, the isolated
diorganylcuprate anions that remain adopt a linear coordination geometry at copper.
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