Carbanions protonation

Statement number 6 has to do with carbon acids and is supported by reference (7). There are, in fact, other references that suggest solvent plays a much more direct role in the kinetics of protonating carbanions than statement number 6 would imply. For example, there is evidence that nuclear reorganization and rehybridization of the carbon atom are too rapid to have much kinetic importance when compared with solvent reorientation. The strong dependence of carbanion protonation rates on the solvent supports this view. These rates are typically much faster in organic solvents, such as DMSO, than in water. A particular reaction that was studied in different solvents (17) is... 

In dissolving-metal ester reduction, the ester carbonyl is believed to accept an electron to form a radical oxyanion 37 (Scheme 12.12). Chelation with a lithium counterion then ensues to produce a tertiary radical 38 which then captures a second electron to become a carbanion. Protonation of 39 next yields 40, whose fate is to collapse to aldehyde 41. Another multiple electron transfer/protonation sequence subsequently yields the product alcohol 46. 

A further complication of the Julia oleflnation is reductive desulfonylation. This process can intervene, especially in substrates where the anti elimination process is less favored, leading to significant amounts of the corresponding desul-fonylated alcohols via carbanion protonation (Eq. 129).226... 

The equilibrium constant for deprotonation of carbon acids is equal to the ratio of the rate constants for formation and reaction of the product carbanion (Scheme I.IA-C). In recent years, kinetic methods have been used to provide solid values of the pKaS for ionization of a wide range of weak carbon acids. These experiments are, in principle, straightforward and require only the determination or estimate of two rate constants - one for the slow and thermodynamically unfavorable generation of the carbanion, and a second for fast downhill carbanion protonation. 

Rate constants for thermodynamically favorable protonation of unstable carbanions are typically very large. These may be determined by direct methods. A description of these direct methods, the most important of which use laser flash photolysis in carbanion generation [29, 30], is outside the scope of this chapter. The indirect methods used to estimate rate constants for carbanion protonation will be described in greater detail, because they provide insight into the nature of the rate determining step for carbanion protonation in water. 

Carbanion protonation in water is a two-step reaction (i) movement of a Bronsted acid into a reactive position, and (ii) proton transfer to carbon. The overall rate constant for carbanion protonation may be limited by either the rate constant for formation of the reactive complex, in which case the overall rate constant for proton transfer can be estimated by using a representative rate constant for the rate-determining transport step, or by the rate constant for proton transfer to carbon. 

Which electrophile is lost from the amino acid residue is, of course, controlled by the enzyme. One way this may occur is by the enzyme binding the PLP imine so that the electrophile is in close proximity to a suitable or base to aid abstraction and also so that the a orbital of the bond to be broken is periplanar with the p r acceptor system, i.e. orthogonal to the plane of the pyridine ring (XXXI). Maximal orbital overlap, stereoelectronic control, will lower the activation energy for the reaction. Aldol-type reactions can also occur with PLP as in the laboratory the key to making carbon-carbon bonds is the formation of a stabilised carbanion. Proton abstraction from the initially formed imine gives a masked carbanion which can nucleophili-... 

Benzyne is electron-deficient and will be attacked by nucleophiles in a reaction that opens the it bond not part of the aromatic cloud, and produces a new carbanion. Protonation completes the sequence to give the aromatic substitution product (Scheme 7.6). Irradiation of either benzocyclobutenedione or phthaloyl peroxide or 3-diazobenzofuranone at 8 K in an argon matrix led to eventual formation of ortHo-benzyne (Scheme 7.7). 

Cytosine also exhibits a single, pH-dependent polarographic reduction wave (Ei/2 = -1.070-0.084) [135]. The basic reaction pattern involved an initial, rapid protonation at the N(3) position to form electroactive species (Fig. lOB). A two-electron reduction of the N(3)=C(4) double bond then occurs to form a carbanion. Protonation... 

A different type of photoreaction in ILs has been studied by Jones and co-workers the photoreduction of benzophenones by primary amines. Prior work by Cohen demonstrated that photolysis of benzophe-none in benzene in the presence of sec-butylamine afforded benzopinacol (and an imine). This reaction proceeds through a radical pair formed by hydrogen-atom abstraction by the triplet excited state ben-zophenone from the amine. In the much more polar environment of an IL, the radical pair may instead undergo single electron transfer to form an iminium cation and a hydroxyl-substituted carbanion. Proton transfer from the cation to the anion will yield benzhydrol and an imine. 

The role of the base is apparently primarily that of a proton remover from the reactive methylene group thus if B represents the base, reaction (i) gives the carbanion, which then combines with the positive carbon of the carbonyl group (reaction ii) the product regains a proton from the piperidinium ion, and then by loss of water followed by mono-decarboxylation of the malonic acid residue gives the final acid. 

The acetylenic proton The carbanion now eliminates Cl to give a most odd-looking carbene. Can you see what it is ... 

The carbanions derived from thioacetals, however, are typical -synthons. Most frequently used are 1,3-dithianes and C -silylated thioethers (see p. 33f. D. Seebach, 1969, 1973 B.-T. Grobel, 1974,1977). In these derivatives the proton is removed by butyllithium in THF. 

An interesting case are the a,/i-unsaturated ketones, which form carbanions, in which the negative charge is delocalized in a 5-centre-6-electron system. Alkylation, however, only occurs at the central, most nucleophilic position. This regioselectivity has been utilized by Woodward (R.B. Woodward, 1957 B.F. Mundy, 1972) in the synthesis of 4-dialkylated steroids. This reaction has been carried out at high temperature in a protic solvent. Therefore it yields the product, which is formed from the most stable anion (thermodynamic control). In conjugated enones a proton adjacent to the carbonyl group, however, is removed much faster than a y-proton. If the same alkylation, therefore, is carried out in an aprotic solvent, which does not catalyze tautomerizations, and if the temperature is kept low, the steroid is mono- or dimethylated at C-2 in comparable yield (L. Nedelec, 1974). 

Carbanions stabilized by phosphorus and acyl substituents have also been frequently used in sophisticated cyclization reactions under mild reaction conditions. Perhaps the most spectacular case is the formation of an ylide from the >S-lactam given below using polymeric Hflnig base (diisopropylaminomethylated polystyrene) for removal of protons. The phosphorus ylide in hot toluene then underwent an intramolecular Wlttig reaction with an acetyl-thio group to yield the extremely acid-sensitive penicillin analogue (a penem I. Ernest, 1979). 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The Birch reductions of C C double bonds with alkali metals in liquid ammonia or amines obey other rules than do the catalytic hydrogenations (D. Caine, 1976). In these reactions regio- and stereoselectivities are mainly determined by the stabilities of the intermediate carbanions. If one reduces, for example, the a, -unsaturated decalone below with lithium, a dianion is formed, whereof three different conformations (A), (B), and (C) are conceivable. Conformation (A) is the most stable, because repulsion disfavors the cis-decalin system (B) and in (C) the conjugation of the dianion is interrupted. Thus, protonation yields the trans-decalone system (G. Stork, 1964B). 

Nonanedione, another 1,3-difunctional target molecule, may be obtained from the reaction of hexanoyl chloride with acetonide anion (disconnection 1). The 2,4-dioxo substitution pattern, however, is already present in inexpensive, symmetrical acetylacetone (2,4-pentanedione). Disconnection 2 would therefore offer a tempting alternative. A problem arises because of the acidity of protons at C-3 of acetylacetone. This, however, would probably not be a serious obstacle if one produces the dianion with strong base, since the strongly basic terminal carbanion would be a much more reactive nucleophile than the central one (K.G. Hampton, 1973 see p. 9f.). 

An important feature of aldol addition is that carbon-carbon bond formation occurs between the a carbon atom of one aldehyde and the carbonyl group of another This is because carbanion (enolate) generation can involve proton abstraction only from the a carbon atom The overall transformation can be represented schematically as shown m Figure 18 5... 

Inductive and resonance stabilization of carbanions derived by proton abstraction from alkyl substituents a to the ring nitrogen in pyrazines and quinoxalines confers a degree of stability on these species comparable with that observed with enolate anions. The resultant carbanions undergo typical condensation reactions with a variety of electrophilic reagents such as aldehydes, ketones, nitriles, diazonium salts, etc., which makes them of considerable preparative importance. 

In theory two carbanions, (189) and (190), can be formed by deprotonation of 3,5-dimethylisoxazole with a strong base. On the basis of MINDO/2 calculations for these two carbanions, the heat of formation of (189) is calculated to be about 33 kJ moF smaller than that of (190), and the carbanion (189) is thermodynamically more stable than the carbanion (190). The calculation is supported by the deuterium exchange reaction of 3,5-dimethylisoxazole with sodium methoxide in deuterated methanol. The rate of deuterium exchange of the 5-methyl protons is about 280 times faster than that of the 3-methyl protons (AAF = 13.0 kJ moF at room temperature) and its activation energy is about 121 kJ moF These results indicate that the methyl groups of 3,5-dimethylisoxazole are much less reactive than the methyl group of 2-methylpyridine and 2-methylquinoline, whose activation energies under the same reaction conditions were reported to be 105 and 88 kJ moF respectively (79H(12)1343). 

As will be pointed out in Section 5.11.3.8.4, epimerization at C(6) under basic conditions involves the formation of a carbanion at C(6). Using Schiff bases to activate the C(6) proton. 

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