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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 1 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. 2 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. 3 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). 4 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 5 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: 6 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. 7 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. 8 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. 9 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. 10 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: 11 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. 12 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. 13 III Semester M Sc – Organic Reactions 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 14 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 15 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: 16 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. 17 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 18 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 19 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 20 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 21 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. 22 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). 23 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 : 24 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 25 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. 26 III Semester M Sc – Organic Reactions 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). 27 III Semester M Sc – Organic Reactions 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 28 III Semester M Sc – Organic Reactions 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. 29 III Semester M Sc – Organic Reactions 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 30 III Semester M Sc – Organic Reactions 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. 31 III Semester M Sc – Organic Reactions 32