The Acidity of an a-Hydrogen

A hydrogen bonded to an sp carbon that is adjacent to a carbonyl carbon, however, is much more acidic than hydrogens bonded to other sp carbons. For example, the pK value for dissociation of a proton from the a-carbon of an aldehyde or a ketone ranges from 16 to 20, and the pK value for dissociation of a proton attached to the a-carbon of an ester is about 25 (Table 18.1). A compound that contains a relatively acidic hydrogen bonded to an sp carbon is called a carbon acid. 

The a-hydrogen of a ketone or an aldehyde is more acidic than the a-hydrogen of an ester. 

A hydrogen bonded to an a-carbon is more acidic than hydrogens bonded to other sp carbons because the base formed when a proton is removed from an a-carbon is relatively stable. And, as we have seen, the more stable the base, the stronger is its conjugate acid (Section 2.6). 

Why is the base formed by removing a proton from an a-carbon more stable than bases formed by removing a proton from other sp carbons When a proton is removed from ethane, the electrons left behind reside solely on a carbon. This localized carbanion is unstable because carbon is not very electronegative. As a result, the of its conjugate acid is very high. 

In contrast, when a proton is removed from an a-carbon, two factors combine to increase the stability of the base that is formed. First, the electrons left behind when the proton is removed are delocalized, and electron delocalization increases stability (Section 8.6). More importantly, the electrons are delocalized onto an oxygen, an atom that is better able to accommodate them because it is more electronegative than carbon. 

---

The abstraction of an a-hydrogen is essential for the deamination process. This can be implied from the fact that tetramethylethylenediamine and a-amino iso-butyric acid do not undergo deamination under the same conditions (11). 

In a number of nonenzymatic reactions catalyzed by pyridoxal, a metal ion complex is formed—a combination of a multivalent metal ion such as cupric oi aluminum ion with the Schiff base formed from the combination of an amino acid and pyridoxal (I). The electrostatic effect of the metal ion, as well as the electron sink of the pyridinium ion, facilitates the removal of an a -hydrogen atom to form the tautomeric Schiff base, II. Schiff base II is capable of a number of reactions characteristic of pyridoxal systems. Since the former asymmetric center of the amino acid has lost its asymmetry, donation of a proton to that center followed by hydrolytic cleavage of the system will result in racemic amino acid. On the other hand, donation of a proton to the benzylic carbon atom followed by hydrolytic cleavage of the system will result in a transamination reaction—that is, the amino acid will be converted to a keto acid and pyridoxal will be converted to pyridoxamine. Decarboxylation of the original amino acid can occur instead of the initial loss of a proton. In either case, a pair of electrons must be absorbed by the pyridoxal system, and in each case, the electrostatic effect of the metal ion facilitates this electron movement, as well as the subsequent hydrolytic cleavage (40, 43). 

As expected, oxidation of a ring sulfur atom to the sulfone derivative enhances the acidity of an a-proton. Thus, hydrogen deuterium exchange of (116) to give (117) occurs with sodium azide in HMPA D20 (30 1) (82TL299). 

The substitution of an a-hydrogen on a carboxylic acid by an amino-group decreases the reactivity. The rate constants of glycine and alanine are 8 x 106 and 6 x 10 M-1 sec-1, respectively (Davis et al., 1965a). This low reactivity of amino acids is expected because they are predominantly in the form of a zwitterion. Other amino acids exhibit higher reactivity, owing to other reactive functional groups (Braams, 1965,... 

The acidity of an acetylenic hydrogen stems from the nature of the sp Formation Of hybrid = C—H bond. Table 9-3 shows how the acidity of a C—H bond varies with. ... ... 

As a synthetic route, this organoborane synthesis parallels the aoetoaoetic ester and malonic ester syntheses. An acetone unit is furnished by acetoacetic ester or, here, by bromoacetone an acetic add unit is furnished by malonic ester or, here, by bromoacetic ester. In these syntheses, bromine plays the same part that the —COOEt group did by increasing the acidity of certain a-hydrogens, it determines where in the molecule reaction will take place it is easily lost from the molecule when its job is done. Unlike the loss of —COOEt, the departure of —Br is an integral part of the alkylation process. 

In view of the acidity of sulfur a-hydrogen atoms, the C(3) hydrogen in 1,2-dithiolanes should be removable by an appropriate base, but no studies are reported. Evidently anions attack predominantly at a ring sulfur atom. 

Carboxylic acids can be brominated at the a-position by reaction with bromine and phosphorus tribromide (PBr3) in the Hell-Volhard-Zelinsky reaction. The reaction, which proceeds via an acid bromide, leads to the substitution of an a-hydrogen atom by a bromine atom. 

Several structural requirements appear to be necessary in order to be able to observe the semibenzilic mechanism. Thus the acidity of the a hydrogen plays an important role. Indeed, it should be weakly acid in order to favor nucleophilic attack at the carbonyl carbon. Of course, this kind of mechanism will be facilitated by the absence of an a hydrogen the rearrangement is then known under the name of quasi-Favorskii. Since both substrates just discussed react via the semibenzilic mechanism, we shall discuss them simultaneously. 

Treatment of a ketone or an aldehyde containing an a hydrogen with halogen (X2, X = I, Cl, or Br) in acid results in the replacement of an a hydrogen with a halogen atom (Fig. 19.33). For the specific example shown in Rgure 19.33, the... 

If the a-carbon is between two carbonyl groups, the acidity of its a-hydrogen is even greater (Table 18.1). For example, the pK value for dissociation of a proton from the a-carbon of 2,4-pentanedione, a compound with an a-carbon between two ketone carbonyl groups, is 8.9. And the pK value for dissociation of a proton from the a-carbon of ethyl 3-oxobutyrate, which is between a ketone carbonyl group and an ester carbonyl group, is 10.7. Ethyl 3-oxobutyrate is classified as a j8-keto ester because the ester has a carbonyl group at the j8-position 2,4-pentanedione is a jS-diketone. 

Claisen condensations in cells result from the condensation of thioesters. The sulfur atom of the thioester is part of a relatively large molecule called coenzyme A. The pA of an a-hydrogen atom of a thioester is about 8.5. It is a hundred times more acidic that the a-hydrogen of P-keto ester. The increased acidity of thioesters results from the ineffective resonance stabihzation of the positive charge of the carbonyl carbon atom by sulfur compared to oxygen. 

Mandelic acid. This preparation is an example of the synthesis of an a-hydroxy acid by the cyanohydrin method. To avoid the use of the very volatile and extremely poisonous hquid hydrogen cyanide, the cyanohydrin (mandelonitrile) is prepared by treatment of the so um bisulphite addition compound of benzaldehj de (not isolated) with sodium cyanide ... 

Diketones 1 can be converted into the salt of an a-hydroxy carboxylic acid upon treatment with alkali hydroxide after acidic workup the free a-hydroxy carboxylic acid 2 is obtained. A well-known example is the rearrangement of benzil (R, R = phenyl) into benzilic acid (2-hydroxy-2,2-diphenyl acetic acid). The substituents should not bear hydrogens a to the carbonyl group, in order to avoid competitive reactions, e.g. the aldol reaction. 

A considerable amount of the strain in l,8-bis(dimethylamino)naphtha-lene is relieved by protonation and the N—H N bond length (260 pm) in the protonated amine shows that the molecule is able to adopt a conformation [55] with an intramolecular hydrogen bond (Truter and Vickery, 1972). The infra-red spectrum of protonated l,8-bis(dimethylamino)naphthalene and the chemical shift (5 19.5) of the acidic proton in the nmr spectrum confirm the presence of an intramolecular hydrogen bond (Alder et al., 1968). The magnitude of the isotope effect on the chemical shift (Altman et al., 1978) and the appearance of two Nls peaks in the photoelectron spectrum... 

---