Acidic a-proton

Dihydro- and 1,4-dihydro derivatives are formed as intermediates in the reduction of quaternary pyridine salts and their homologues with sodium borohydride or formic acid. A proton is added to the present enamine grouping and the formed immonium salts are reduced to the l-methyl-l,2,5,6-tetrahydropyridine derivatives (157) and to completely saturated compounds (158) (254) (Scheme 14). 

D-Methylmalonyl-CoA, the product of this reaction, is converted to the L-isomer by methylmalonyl-CoA epunerase (Figure 24.19). (This enzyme has often and incorrectly been called methylmalonyl-CoA racemase. It is not a racemase because the CoA moiety contains five other asymmetric centers.) The epimerase reaction also appears to involve a carbanion at the a-position (Figure 24.20). The reaction is readily reversible and involves a reversible dissociation of the acidic a-proton. The L-isomer is the substrate for methylmalonyl-CoA mutase. Methylmalonyl-CoA epimerase is an impressive catalyst. The for the proton that must dissociate to initiate this reaction is approximately 21 If binding of a proton to the a-anion is diffusion-limited, with = 10 M sec then the initial proton dissociation must be rate-limiting, and the rate constant must be... 

Base abstracts an acidic a proton from the carbon atom next to one of the ester groups, yielding an enolate ion. 

The side-chain carboxylate group of an aspartic acid acts as a base and removes an acidic a proton from acetyl CoA, while the N-H group on the side chain of a histidine acts as an acid and donates a proton to the car bonyl oxygen, giving an enol. 

A proton (H+) is an electron pair acceptor. It is therefore a Lewis acid because it can attach to ( accept") a lone pair of electrons on a Lewis base. In other words, a Bronsted acid is a supplier of one particular Lewis acid, a proton. The Lewis theory is more general than the Bronsted-Lowry theory. For instance, metal atoms and ions can act as Lewis acids, as in the formation of Ni(CO)4 from nickel atoms (the Lewis acid) and carbon monoxide (the Lewis base), but they are not Bronsted acids. Likewise, a Bronsted base is a special kind of Lewis base, one that can use a lone pair of electrons to form a coordinate covalent bond to a proton. For instance, an oxide ion is a Lewis base. It forms a coordinate covalent bond to a proton, a Lewis acid, by supplying both the electrons for the bond ... 

Bronsted acid A proton donor (a source of hydrogen ions, H+). Examples HC1 CH COOH HCO - NH4 ... 

The intramolecular asymmetric Stetter reaction of aliphatic aldehydes is generally more difficult to achieve due to the presence of acidic a-protons. Rovis and co-workers have demonstrated that the NHC derived from pre-catalyst 130 promotes the intramolecular Stetter cyclisation with enoate and alkyhdene malonate Michael acceptors 133. Cyclopentanones are generally accessed in excellent yields and enantioselectivities, however cyclohexanones are obtained in significantly lower yields unless very electron-deficient Michael acceptors are employed... 

As emphasized above, the practical utility of organocerium compounds is to circumvent the problems which are faced with the corresponding Grignard and organolithium reagents because of their inability to react effectively with sterically demanding carbonyl compounds and carbon-heteroatom unsaturated bonds which have acidic a-protons. Some of the latest examples are shown below. 

An ethynylcerium reagent was effectively utilized in the last step for the total synthesis of desogestrel 17.12 Desogestrel was isolated in 92% yield from the corresponding ketone 16, bearing acidic a-protons (Equation (2)). 

Amino acid A Proton affinity (kcal mol ) Threshold iicom (eV)... 

Primary and secondary nitroalkanes, and substrates containing terminal em-dinitroaliphatic functionality, have one or more acidic a-protons, a consequence of inductive and resonance effects imposed by the nitro group. As a result, such compounds can behave like carbanions and participate in a number of addition and condensation reactions which are typical of substrates like ketones, aldehydes, and /S-ketoesters. Such reactions are extremely useful for the synthesis of functionalized polynitroaliphatic compounds which find potential use as explosives, energetic oligomers and plasticizers. 

Both the Henry reaction and the reverse demethylolation are synthetically useful in the chemistry of polynitroaliphatic compounds. The Henry reaction is commonly used to mask the natural chemistry of an aliphatic nitro or terminal em-dinitro group by removing the acidic a -proton(s). In Section 1.7 we discussed the conversion of Q ,ty-dinitroalkanes to their bis-methylol derivatives before subjecting them to oxidative nitration and subsequent demethylolation with base, a procedure which results in the formation of Q ,Q , y, y-tetranitroalkanes. ... 

Metabolic derivatives of pantothenic acid are of fundamental importance in acyl transfer reactions and in condensation reactions requiring an acidic a-proton. The... 

Similar chemistry is possible starting from hydrazones bearing acidic a protons an initial diastereoselective enolization and electrophilic functionalization of the hydrazone can be followed by derivatization which is stereoselective in the planar sense . ... 

Little information concerning the reactivity of this system was included in either CHEC(1984) or CHEC-II(1996). However, a variety of results have been appeared in the past decade. Pyrazino[2,3-dpyridazines undergo nucleophilic substitution at C-3 (Scheme 26) <1997JHC39> and at CM (Scheme 27) <2005W02005/099710>. In the presence of acid, a protonated dibenzannulated species is susceptihle to nucleophilic addition (Scheme 28) the quinonoid adduct is air stable as a salt, but aromatizes in the presence of base <1996J(P1)1699>. The process is unaffected by... 

The deprotonation of Af-alkyl imines 1 with LDA to give 2-azaallyl anions 2 is a well-known reaction34 At least one stabilizing substituent R2 such as phenyl35 or alkoxycarbonyl36 at the carbon atom is necessary to achieve the deprotonation. The deprotonation of iV-benzylimines, which contain no acidic a-protons in the R1 group proceeds under relatively mild conditions37-38. 

Phenylsulfonylcyclobutanes have sufficiently acidic a-protons to undergo a-alkylation reactions. For example, phenylsulfonylcyclobutane, on alkylation with l-bromo-4-methylpent-2-ene gave l-(4-methylpent-2-cnyl)-1-phenylsulfonylcyclobutane (8),152 and (1R, 2S, 3S )-1,2-dimethyl-3-phenylsulfonylcyclobutane gave (l/ , 2/ , 3S )-l-(l-acetoxy-2-methylpropyl)-2,3-dimethyl-1-phenylsulfonylcyclobutane (9) on reaction with isobutyraldehyde followed by treatment with acetic anhydride.133... 

In a solvent with weak acidity, the solvent molecule cannot easily release a proton. Thus, the pH region is wider on the basic side than in water some strong bases, whose strengths are leveled in water, are differentiated some very weak acids, which cannot be determined by neutralization titration in water, can be determined. In contrast, in a solvent with strong acidity, a proton is easily released from the solvent molecule. Thus, the pH region is narrow on the basic side strong bases are easily leveled neutralization titrations of very weak acids are impossible. 

Brpnsted and Lowry classified acids as proton donors and bases as proton acceptors. HC1 is an acid (a proton donor) and it increases the concentration of H30+ in water ... 

Brpnsted-Lowry acid A proton (hydrogen ion) donor. 

The sulfonyl group is a key feature in the preparation of the unusually substituted dithiin sulfone (174) from dibenzyl sulfone. The acidic a-protons are abstracted with sodium hydride and the carbanionic intermediates react with carbon disulfide. The reaction is quenched with methyl iodide to give (174) in 17% yield (73BSF637). Another multisubstituted dithiin (175) is available from the reaction of diphenylthiirene dioxide with the ylide (176) (Scheme 21) but again the yield is low. However, the reaction is of particular interest in so far as the product mixture also contains a derivative of the rare oxathiin nucleus. Indeed of the three products isolated the oxathiin sulfone (177) is formed in marginally the highest yield (73BCJ667). 

The use of an a-isocyanoacetamide instead of an a-isocyanoacetate is essential in order to obtain oxazoles when the latter compounds are employed, other condensations (Knoevenagel, Mannich), affording imidazolines or amidines, will take place [88]. This reaction has been explored for the preparation of a series of 2-imidazolines employing isocyanoacetates [91]. The reaction worked smoothly to give compounds 105a,b (Scheme 1.36) with the trans isomer prevailing, provided that a racemic isocyanide with an acidic a-proton and a sterically undemanding amine are used. 

The first step is a nucleophilic substitution of bromide by triphenylphosphine. Treatment of the derived triphenylphosphonium salt with base removes the relatively acidic a proton, forming the ylide. (For a review of ylide formation, refer to Section 17.12.)... 

The —NH2 group is more basic than the -C02 group. Thus, on treatment with acid (as in Problem 17.1), a proton adds first to the -NH2 group. Then, with a second equivalent of acid, a proton adds to the -C02 group. 

DKR of thioesters (Scheme 21.2) with a chiral center at the a-carbon has been achieved in a water/acetonitrile biphasic system by racemization with mild organic bases, such as trioctylamine, coupled to enantioselective hydrolysis of the thioester with subtilisin Carlsberg.28 Such an approach can be applied to a wide variety of thioesters but not oxoesters, which have less acidic a-protons. 

Treatment with a base results in loss of one of the acidic a protons ... 

A third method of access to sulfines is the oxidation of thiocarbonyl compounds. When the starting material is available it is an attractive route. There has been some dispute in the past whether enethiolisable thiocarbonyl derivatives would lead to the corresponding sulfines or to divinyl disulfides [101, 102]. It is now clear from our research that, even if the C=S molecules bear highly acidic a-protons, oxidation occurs on C=S and does not touch the a-protons. There are many examples of this behaviour. The most easily enethiolised compounds are thioketones. We have shown that their reaction with a peroxycarboxylic acid, mCPBA, is very fast at 0°C and quantitatively provides the corresponding sulfines [103]. In many examples the aliphatic sulfines are not very stable and have to be used in subsequent reactions that will be faster than their decomposition (t1/2 from some hours to days). 

In the presence of strong bases, ketones and aldehydes act as weak proton acids. A proton on the a carbon atom is abstracted to form a resonance-stabilized enolate ion with the negative charge spread over a carbon atom and an oxygen atom. Reprotonation can occur either on the a carbon (returning to the keto form) or on the oxygen atom, giving a vinyl alcohol, the enol form. 

Keto-enol tautomerism is also catalyzed by acid. In acid, a proton is moved from the a carbon to oxygen by first protonating oxygen and then removing a proton from carbon. 

This is a matter of acidity. The more acidic a proton is-—that is, the more easily it releases H+ (this is the definition of acidity from Chapter 8)—the more the OH bond is polarized towards oxygen. The more the RO-H bond is polarized, the closer we are to free H+, which would have no shielding electrons at all, and so the further the proton goes downfield. The OH chemical shifts and the acidity of the OH group are very roughly related. 

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